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WO2020081880A1 - Compositions ciblant des cellules sénescentes et leurs utilisations - Google Patents

Compositions ciblant des cellules sénescentes et leurs utilisations Download PDF

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Publication number
WO2020081880A1
WO2020081880A1 PCT/US2019/056837 US2019056837W WO2020081880A1 WO 2020081880 A1 WO2020081880 A1 WO 2020081880A1 US 2019056837 W US2019056837 W US 2019056837W WO 2020081880 A1 WO2020081880 A1 WO 2020081880A1
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Prior art keywords
compound
bcl
senolytic agent
cells
formula
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Inventor
Daohong Zhou
Guangrong Zheng
Xuan Zhang
Yingying Wang
Jianhui CHANG
Fen XIA
Maria Schuller ALMEIDA
Ha-Neui Kim
Peiyi Zhang
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BioVentures LLC
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BioVentures LLC
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Priority claimed from US16/165,797 external-priority patent/US20190054097A1/en
Application filed by BioVentures LLC filed Critical BioVentures LLC
Publication of WO2020081880A1 publication Critical patent/WO2020081880A1/fr
Anticipated expiration legal-status Critical
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present disclosure relates to compositions and methods which target senescent cells.
  • the present disclosure provides compositions which inhibit or induce the degradation of anti-apoptotic Bcl-2 family proteins and their method of use in the treatment of various cancers and treatment and prevention of diseases and pathologies related to accumulation of senescent cells during aging, such as aging, cancer, chronic obstructive pulmonary disease (COPD), osteoporosis, osteoarthritis, atherosclerosis, neurodegenerative diseases, diabetes, and many others.
  • COPD chronic obstructive pulmonary disease
  • osteoporosis osteoarthritis
  • atherosclerosis atherosclerosis
  • neurodegenerative diseases diabetes, and many others.
  • the present invention also relates to pharmaceutical compositions containing these compounds as well as various uses thereof.
  • Aging is the major risk factor for most functional deficits and many diseases in human, such as cancers, osteoarthritis, osteoporosis, atherosclerosis, neurodegenerative diseases, and diabetes.
  • An increasing body of evidence demonstrates that aging is associated with an accumulation of senescent cells
  • Senescent cell accumulation in tissues and organs is believed to cause tissue degradation and loss of function due to the increased levels of free radicals and various inflammatory mediators produced by senescent cells. Therefore, selective depletion of senescent cells may be a novel antiaging strategy that may prevent cancer and various human diseases associated with aging and rejuvenate the body to live a healthier lifespan.
  • the number of senescent cells increases in bone with age.
  • Age-related bone loss is associated with an increase in the number of cells that resorb bone (osteoclasts) and a decrease in the cells that form bone (osteoblasts).
  • Osteoblast senescence decreases cell number and increases the secretion of factors which promote osteoclast formation causing bones to become weak and brittle.
  • Bone fractures caused by osteoporosis lead to severe restriction on activity. In particular, hip fracture is involved in high mortality of about 15 to 35%. Therefore, it is important to diagnose and treat osteoporosis prior to occurrence of osteoporotic fractures
  • bisphosphonate-based medicines have been known as medicines for treating osteoporosis. It is known that bisphosphonate sticks to an inorganic element of bone and when an osteoclast resorbs the bone to which bisphosphonate sticks, a non-hydrolyzed ATP analogue is formed and exhibits toxicity on the cell or causes a decrease in activity of the osteoclast and apoptosis in various ways in the osteoclast, thereby reducing bone resorption and thus increasing a bone density.
  • PN Peripheral neuropathy
  • CIPN chemotherapy-induced PN
  • the peripheral nervous system consists of sensory neurons running from stimulus receptors that inform the central nervous system (CNS) of the stimuli, and motor neurons running from the spinal cord to the effectors that take action.
  • CNS central nervous system
  • an anticancer drug could impair both sensory and motor functions. It can include sharp, stabbing pain, hearing loss, blurred vision and change in taste.
  • the motor neuron dysfunction manifest as cramps, difficulty with fine motor activities (e.g. writing), gait disturbances, paralysis, spasms, tremors and weakness.
  • CIPN may result from the use of numerous chemotherapeutic agents, including, but not limited to, Ixabepilone (Ixempra Kit), arsenic trioxide
  • chemotherapeutic drugs that most commonly elicit CIPN include platinum compounds (cisplatin, carboplatin, oxaliplatin), vincristine, taxanes (docetaxel, paclitaxel), epothilones (ixabepilone), bortezomib (Velcade), thalidomide (Thalomid) and lenalidomide.
  • CIPN symptoms are commonly managed in a manner similar to other types of nerve pain-that is, with a combination of physical therapy,
  • the Bcl-2 (B-cell lymphoma-2) family of proteins is a group of regulator proteins that plays a central role in regulating cell death by either inducing (pro-apoptotic) or inhibiting (anti-apoptotic) apoptosis.
  • Anti-apoptotic Bcl-2 family of proteins such as Bcl-2, Bcl-xL, Bcl-W, and Mcl-1 , has been proven to be an attractive target for the development of novel anti-cancer agents (Lessene et al., Nat. Rev. Drug Discov. 7:989-1000, 2008; Vogler et al., Cell Death Differ. 2009;16:360-367; Delbridge et al., Nat. Rev.
  • the Bcl-2 family of proteins has also been found to be a potential target for the development of“senolytic” drugs, drugs that targeting senescent cells for the delay of aging or treatment of aging-associated disease.
  • navitoclax ABT-263
  • Bcl-xL Bcl-xL
  • Bcl-W navitoclax
  • compositions and methods of killing one or more senescent cells in a subject comprising
  • R 1 is selected from the group consisting of:
  • R 3 is absent, a bond, or a substituted or unsubstituted C 1 -C 10 alkyl
  • A is absent, a bond, a substituted or unsubstituted CrC 6 aryl, a substituted or unsubstituted CrC 6 cycloalkyl, or a substituted or unsubstituted CrC 6 heterocyclic group;
  • R 4 is a bond or a substituted or unsubstituted C 1 -C 10 alky; n is an integer from 0 to 5; R 2 is selected from the group consisting
  • the invention encompasses a method for delaying at least one feature of aging in a subject.
  • the method comprises administering a therapeutically effective amount of a compound of the invention to a subject in need thereof.
  • the invention encompasses a method of treating an age-related disease or condition.
  • the method comprises administering a therapeutically effective amount of a compound of the invention to a subject in need thereof.
  • the invention encompasses a method of killing therapy-induced senescent cells.
  • the method comprises administering a therapeutically effective amount of a compound of the invention to a subject in need thereof who has received DNA-damaging therapy and killing therapy induced-senescent cells in normal and tumor tissues following DNA-damaging therapy.
  • FIG. 1 A and FIG. 1 B depicts graphs that show XZ-13906 (2 mM) depletes Bcl-xL in normal WI38 (NC-WI38) and ionizing radiation induced senescent WI38 (IR-SC WI38 cells).
  • FIG. 2A and FIG. 2B depicts graphs show that compound 11 (XZ- 13861 ) (FIG. 2A) and XZ-13906 (FIG. 2B) selectively inhibits IR-SC WI38 cells but not normal WI38 cells in a dose-dependent manner.
  • FIG. 3A and FIG. 3B depicts graphs that show that XZ-14439 dose dependent (FIG. 3A) and time dependency (FIG. 3B) depletes Bcl-xL in IR-SC WI38 cells.
  • FIG. 4A and FIG. 4B depicts graphs that show that XZ-1 541 6, XZ-
  • FIG. 5 shows the clearance of senescent cells with ABT263 reversed
  • Cisplatin-induced peripheral neuropathy in C57BL/6 mice.
  • CIPN Cisplatin-induced peripheral neuropathy
  • CIPN was induced in young adult male and female C57BL/6 mice by intraperitoneal (i.p.) injection of Cisplatin (Lake Zurich, IL, USA) at 2.3 mg/kg/d for 5 days per cycle for 2 cycles with an interval of 5 days between the cycles.
  • the induction of CIPN was measured by analyzing the mechanical sensitivity using the Von Frey assay the day before Cisplatin treatment and on various day after Cisplatin treatment
  • FIG. 6 depicts the data from FIG. 5 in a bar graph to show statistical differences among the different treatment groups.
  • N 10 for control group and 5 for Cisplatin- treated groups. ** and *** p ⁇ 0.01 and 0.001 , respectively, vs. Control.
  • FIG. 8 shows both genetic and pharmacological clearance of senescent cells with ganciclovir (GCV) and ABT263, respectively, reversed cisplatin-induced peripheral neuropathy (CIPN) in p16-3MR transgenic mice.
  • CIPN was induced in young adult male and female p16-3MR mice by intraperitoneal (i.p.) injection of cisplatin (Lake Zurich, IL, USA) at 2.3 mg/kg/d for 5 days per cycle for 2 cycles with an interval of 5 days between the cycles.
  • the induction of CIPN was measured by analyzing the mechanical sensitivity using the Von Frey assay the day before Cisplatin treatment and on various day after Cisplatin treatment.
  • N 5-6 mice per group.
  • FIG. 9 depicts data from FIG. 8 in a bar graph to show statistical differences among the different treatment groups.
  • N 5-6 mice per group. * , ** and *** p ⁇ 0.05, 0.01 , and 0.001 , respectively, vs. Saline or Saline + GCV group.
  • GCV ganciclovir
  • ABT263 reversed cisplatin-induced peripheral neuropathy
  • FIG. 11 depicts the data from FIG. 10 in a bar graph to show statistical differences among the different treatment groups.
  • N 5-6 mice per group. . * , ** and *** p ⁇ 0.05, 0.01 , and 0.001 , respectively, vs. Saline or Saline + GCV group.
  • FIG. 12A and FIG. 12B show five-day administration of ABT-263 or Bcl-
  • FIG. 12A shows a western blot analysis of markers of DNA damage (g-H2AC) and cellular senescence (GATA4 and p16), each lane represents one animal.
  • FIG. 13 shows five-day administration of ABT-263 or Bcl-PROTAC eliminates osteoprogenitor senescence and SASP in aged mice. mRNA levels by qRT-PCR in bone marrow stromal cells from 24-month-old female mice cultured with ascorbate and b- glycerophosphate for 7 days (triplicate cultures), * p ⁇ 0.05.
  • FIG. 14A, FIG. 14B and FIG. 14C show five-day administration of ABT-
  • FIG. 14A shows Alizarin Red staining and FIG. 14B depicts quantification in stromal cells cultured with ascorbate and b- glycerophosphate for 21 d.
  • FIG. 14C shows the quantification of Oil Red O staining in stromal cells cultured with rosiglitazone for 1 1 d. Triplicate cultures; * p ⁇ 0.05
  • FIG. 15A and FIG. 15B show five-day administration of ABT-263 or Bcl-
  • FIG. 15A depicts representative pictures of TRAP-positive multinucleated cells generated from bone marrow macrophages.
  • FIG. 15B show TRAP-positive multinucleated cells containing three or more nuclei were counted as osteoclasts (triplicate cultures). * p ⁇ 0.05.
  • the present invention relates to compounds which are capable of degrading the Bcl-2 family of proteins.
  • the bivalent compounds connect a Bcl-2 small molecule inhibitor or ligand to an E3 ligase binding moiety, such as cereblon (CRBN) E3 ligase binding moiety (thalidomide derivatives such as pomalidomide) or von Hippel-Landau (VHL) E3 ligase binding moiety (such as HIF-1 a-derived (R)- hydroxyproline containing VHL E3 ligase ligands).
  • CRBN is part of the cullin-4 (CUL4) containing E3 ubiquitin ligase complex CUL4-RBX1 -DDB1 -CRBN (known as
  • CRL4CRBN Thalidomide and its derivatives, such as lenalidomide and pomalidomide, interact specifically with this CRBN complex and inducing degradation of essential IKAROS transcription factors.
  • VHL is part of the cullin-2 (CUL2) containing E3 ubiquitin ligase complex elongin BC-CUL2-VHL (known as CRL2VHL) responsible for degradation of the transcription factor HIF-1 a.
  • CUL2VHL cullin-2
  • (R)-Hydroxyproline containing VHL E3 ligase ligands derived from HIF-1 a have been identified with high affinity.
  • the bivalent compounds can actively recruit the Bcl-2 family of proteins to an E3 ubiquitin ligase, such as CRBN or VHL E3 ligase, resulting in their degradation by ubiquitin proteasome system.
  • Senescent cells can cause chronic inflammation and oxidative stress through expression of senescence-associated secretory phenotype (SASP) and production of reactive oxygen species (ROS).
  • SASP senescence-associated secretory phenotype
  • ROS reactive oxygen species
  • the expression of SASP and production of ROS may contribute to CIPN.
  • clearance of SCs with a senolytic agent that can selectively kill SCs provides a novel therapeutic strategy to prevent, mitigate and treat CIPN.
  • the present invention is directed to a method for the treatment of chemotherapy induced peripheral neuropathy comprising the step of administering to a subject in need thereof a therapeutically-effective amount of a small molecule senolytic agent that selectively kills senescent cells over non-senescent cells.
  • senolytic agents include, but are not limited to, MDM2 inhibitors (e.g., nutlin 3a, RG-71 12); inhibitors of one or more BCL-2 anti- apoptotic protein family members, which inhibitors inhibit a function of at least the anti- apoptotic protein, BCL-xL (e.g., ABT-263, ABT-737, WEHI-539, A-1 155463); and Akt specific inhibitors (e.g., MK-2206). Senolytic agents described herein are sufficient to kill significant numbers of senescent cells.
  • MDM2 inhibitors e.g., nutlin 3a, RG-71 12
  • BCL-2 anti- apoptotic protein family members which inhibitors inhibit a function of at least the anti- apoptotic protein
  • BCL-xL e.g., ABT-263, ABT-737, WEHI-539, A-1 155463
  • Akt specific inhibitors e.g., MK
  • a composition of the invention comprises a compound of Formula (I) or a compound of Formula (II).
  • Derivatives of Formula (I) or Formula (II) may be made to improve potency, bioavailability, solubility, stability, handling properties, or a combination thereof, as compared to an unmodified version.
  • a composition of the invention may optionally comprise one or more additional drugs or therapeutically active agents in addition to a compound of Formula (I) or a compound of Formula (II).
  • a composition of the invention may further comprise a pharmaceutically acceptable excipient, carrier or diluent.
  • a composition of the invention may contain preserving agents, solubilizing agents, stabilizing agents, wetting agents, emulsifiers, sweeteners, colorants, odorants, salts (substances of the present invention may themselves be provided in the form of a pharmaceutically acceptable salt), buffers, coating agents or antioxidants.
  • R is a protein targeting unit which binds to one or more anti-apoptotic Bcl- 2 family of proteins
  • L is a linker unit which covalently links R and R 2 through an alkyl, branched alkyl, ether, thioether, ester, amine, amide, carbamate, carbamide, sulfone, aryl, heteroaryl, cycloalkyl, or heterocyclic group, both end can be same or different;
  • the linker unit could contain a combination of two or more groups among alkyl, branched alkyl, ether, thioether, ester, amine, amide, carbamate, carbamide, sulfone, aryl, heteroaryl, cycloalkyl, and heterocyclic groups;
  • the linker unit comprises a length of 1 -30 atoms in shortest length; and
  • R 2 is an E3 ubiquitin ligase binding unit which binds to the CRBN or VHL E3 ubiquitin ligase.
  • R 1 is selected from the group consisting of:
  • R 3 is absent, a bond, or a substituted or unsubstituted C 1 -C 10 alkyl;
  • A is absent, a bond, a substituted or unsubstituted CrC 6 aryl, a substituted or unsubstituted CrC 6 cycloalkyl, a substituted or unsubstituted CrC 6 heterocyclic group;
  • R 4 is a bond or a substituted or unsubstituted C 1 -C 10 alky
  • n is an integer from 0 to 5;
  • R 2 is selected from the group consisting of
  • a compound of Formula (II) comprises any of the preceding compounds of Formula (II), wherein Ft 1 may be
  • a compound of Formula (II) comprises any of the preceding compounds of Formula (II), wherein R 3 may be absent, an unsubstituted CrC 6 alkyl, or a substituted or unsubstituted C 3 -C 6 ketone.
  • a compound of Formula (II) comprises any of the preceding compounds of Formula (II), wherein R 3 may be absent, a bond, an unsubstituted C1-C3 alkyl, or an unsubstituted C 3 -C 6 ketone.
  • a compound of Formula (II) comprises any of the preceding compounds of Formula (II), wherein R 3 may be absent, a bond, 2-pentanone, or an unsubstituted C 2 -C 3 alkyl.
  • a compound of Formula (II) comprises any of the preceding compounds of Formula (II), wherein A may be absent, a bond, or a substituted or unsubstituted CrC 6 heterocyclic group.
  • a compound of Formula (II) comprises any of the preceding compounds of Formula (II), wherein A may be absent, a bond, or an unsubstituted C 5 heterocyclic group.
  • a compound of Formula (II) comprises any of the preceding compounds of Formula (II), wherein A may be absent, a bond, or a triazole.
  • a compound of Formula (II) comprises any of the preceding compounds of Formula (II), wherein n may be 0 to 3.
  • a compound of Formula (II) comprises any of the preceding compounds of Formula (II), wherein n may be 0 to 2.
  • a compound of Formula (II) comprises any of the preceding compounds of Formula (II), wherein n may be 1 to 2.
  • a compound of Formula (II) comprises any of the preceding compounds of Formula (II), wherein R 4 may be a bond or a substituted or unsubstituted CrCi 0 alkyl.
  • a compound of Formula (II) comprises any of the preceding compounds of Formula (II), wherein R 4 may be a bond or a substituted C1-C10 alkyl.
  • a compound of Formula (II) comprises any of the preceding compounds of Formula (II), wherein R 2 is
  • a compound of the disclosure comprises wo 2020/081880
  • R 2 may be any suitable substituted or unsubstituted CrC 6 alkyl, or a substituted or unsubstituted C 3 -C 6 ketone;
  • A may be absent, a bond, or a substituted or unsubstituted C r C 6 heterocyclic group;
  • n may be 0 to 3;
  • R 4 may be a bond or a substituted or unsubstituted C r Cio alkyl; and R 2 may be
  • a compound of the disclosure comprises
  • A may be absent, a bond, or a substituted or unsubstituted CrC 6 heterocyclic group; n may be 0 to 3, R 4 may be a bond or a substituted or unsubstituted C 1 -C 10 alkyl; and R 2 may be
  • nd 2- pentanone, or an unsubstituted C 2 -C 3 alkyl
  • B may be absent, a bond, or a substituted or unsubstituted C C 6 heterocyclic group
  • n may be 0 to 3
  • R 4 may be a bond or a
  • R 2 may
  • a compound of the disclosure comprises Formula (II), wherein R 1 may Wo
  • CrC 6 alkyl or a substituted or unsubstituted C 3 -C 6 ketone
  • A may be absent, a bond, or a triazole
  • n may be 0 to 3
  • R 4 may be a bond or a substituted or unsubstituted C r Ci 0
  • CrC 6 alkyl or a substituted or unsubstituted C 3 -C 6 ketone
  • A may be absent, a bond, or a substituted or unsubstituted CrC 6 heterocyclic group
  • n may be 1 to 2
  • R 4 may be a bond or a substituted or unsubstituted C 1 -C 10 alkyl
  • R 2 may be
  • a compound of the disclosure comprises Formula (II), wherein R 1 may Wo
  • CrC 6 alkyl or a substituted or unsubstituted C 3 -C 6 ketone
  • A may be absent, a bond, or a substituted or unsubstituted CrC 6 heterocyclic group
  • n may be 0 to 3
  • R 4 may be a bond or a substituted C r Ci 0 alkyl
  • R 2 may
  • CrC 6 alkyl or a substituted or unsubstituted C 3 -C 6 ketone
  • A may be absent, a bond, or a substituted or unsubstituted CrC 6 heterocyclic group
  • n may be 0 to 3
  • R 4 may be a bond or a substituted or unsubstituted C1-C10 alkyl
  • R 2 may be
  • R 1 may be propyl
  • n may be 2
  • A may be a triazole
  • R 4 may be a bond
  • R 2 may be
  • R 1 may be propyl
  • n may be 2
  • A may be a triazole
  • R 4 may be a bond
  • R 2 may be
  • R 1 may be butan-1 -amine; A may be absent; n may be 2; R 4 may be N-(4-
  • R may be C(O); n may be 1 ; A may be absent; R may be a bond; and R may be
  • R 3 may be C(O); n may be 2; A may be absent; R 4 may be a bond; and R 2 may be
  • R may be C(O); n may be 3; A may be absent; R may be a bond; and R may be
  • R 3 may be C(O); n may be 0; A may be absent; R 4 may be a bond; and R 2 may be
  • R 3 may be a bond; A may be absent; n may be 2; R 4 may be a bond; and R 2 may be
  • R 3 may be 2-pentanone; A may be a triazole; n may be 2; R 4 may be a bond; and R 2
  • R 3 may be 2-pentanone; A may be a triazole; n may be 2; R 4 may be a bond; and R 2
  • N-ethylpropionamide may be N-ethylpropionamide; A may be a triazole; n may be 2; R 4 may be a bond; and
  • R 2 may be propyl; A may be triazole; n may be 3; R 4 may be a bond; and R 2 may be
  • a compound of the disclosure comprises Formula (II), wherein R 1 may be
  • a compound of the disclosure comprises Formula (II), wherein R 1 may be
  • a compound of the disclosure comprises Formula (II), wherein R 1 may be
  • a compound of the disclosure comprises Formula (II), wherein R 1 may be
  • a compound of the disclosure comprises Formula (II), wherein R 1 may be
  • R 1 may be
  • N-methylacetamide may be a triazole; n may be 2; R 4 may be a bond; and R 2 may be
  • R 2 may by 2-pentanone; A may be a triazole; n may be 1 ; R 4 may be a bond; and R 2 may be
  • a compound of Formula (II) comprises any of the preceding compounds of Formula (II), may be selected from the group consisting of:
  • ABT-263 is also known as Navitoclax in the art and is known to be useful as an inhibitor of Bcl-2, Bcl-w and, Bcl-xL.
  • ABT263 administration of ABT263 to subjects has been shown to cause thrombocytopenia as platelets also rely on Bcl-xl for survival.
  • Compounds of Formula (I) and Formula (II) of the present invention through in-part, the selection of a proper E3 ligase ligand, add an extra layer of selectivity to the senolytic agents that result in minimum degradation effects on Bcl-xl proteins in platelets compared with ABT263.
  • a senolytic agent as used herein is an agent that "selectively" (preferentially or to a greater degree) destroys, kills, removes, or facilitates selective destruction of senescent cells.
  • the senolytic agent destroys or kills a senescent cell in a biologically, clinically, and/or statistically significant manner compared with its capability to destroy or kill a non-senescent cell.
  • a senolytic agent is used in an amount and for a time sufficient that selectively kills established senescent cells but is insufficient to kill (destroy, cause the death of) a non-senescent cell in a clinically significant or biologically significant manner.
  • the senolytic agents described herein alter at least one signaling pathway in a manner that induces (initiates, stimulates, triggers, activates, promotes) and results in (i.e., causes, leads to) death of the senescent cell.
  • the senolytic agent may alter, for example, either or both of a cell survival signaling pathway (e.g., Akt pathway) or an inflammatory pathway, for example, by antagonizing a protein within the cell survival and/or inflammatory pathway in a senescent cell.
  • the mechanism by which the inhibitors and antagonists described herein selectively kill senescent cells is by inducing (activating, stimulating, removing inhibition of) an apoptotic pathway that leads to cell death.
  • Non-senescent cells may be proliferating cells or may be quiescent cells.
  • exposure of non-senescent cells to the senolytic agent as used in the methods described herein may temporarily reduce the capability of non- senescent cell to proliferate; however, an apoptotic pathway is not induced and the non- senescent cell is not destroyed.
  • Certain senolytic agents that may be used in the methods described herein have been described as useful for treating a cancer; however, in the methods for treating a senescence associated disorder or disease, the senolytic agents are administered in a manner that would be considered different and likely ineffective for treating a cancer.
  • the method used for treating chemotherapy-induced peripheral neuropathy with a senolytic agent described herein may comprise one or more of a decreased daily dose, decreased cumulative dose over a single treatment cycle, or decreased cumulative dose of the agent from multiple treatment cycles than the dose of an agent required for cancer therapy; therefore, the likelihood is decreased that one or more adverse effects (i.e., side effects) will occur, which adverse effects are associated with treating a subject according to a regimen optimized for treating a cancer.
  • the compounds described herein may be administered at a lower dose than presently described in the art or in a manner that selectively kill senescent cells (e.g., intermittent dosing).
  • the senolytic agents described herein may be administered at a lower cumulative dose per treatment course or treatment cycle that would likely be insufficiently cytotoxic to cancer cells to effectively treat the cancer.
  • the senolytic agent is not used in a manner that would be understood by a person skilled in the art as a primary therapy for treating a cancer, whether the agent is administered alone or together with one or more additional chemotherapeutic agents or radiotherapy to treat the cancer.
  • an agent as used in the methods described herein is not used in a manner that is sufficient to be considered as a primary cancer therapy, the methods and senolytic combinations described herein may be used in a manner (e.g., a short term course of therapy) that is useful for inhibiting
  • a "primary therapy for cancer” as used herein means that when an agent, which may be used alone or together with one or more agents, is intended to be or is known to be an efficacious treatment for the cancer as determined by a person skilled in the medical and oncology arts, administration protocols for treatment of the cancer using the agent have been designed to achieve the relevant cancer-related endpoints.
  • a senolytic agent may be administered at a site proximal to or in contact with senescent cells (not tumor cells). Localized delivery of senolytic agents is described in greater detail herein.
  • a senolytic agent as used in the methods described herein is a small molecule compound. These senolytic agents that are small molecules may also be called herein senolytic compounds.
  • the senolytic agents that are small molecules include those that are activated or that are pro-drugs which are converted to the active form by enzymes within the cell.
  • the enzymes that convert a pro-drug to an active senolytic form are those expressed at a higher level in senescent cells than in non-senescent cells.
  • Senolytic agents described herein that may alter at least one signaling pathway include an agent that inhibits an activity of at least one of the target proteins within the pathway.
  • the senolytic agent may be a specific inhibitor of one or more BCL-2 anti-apoptotic protein family members wherein the inhibitor inhibits at least BCL-xL (e.g., a Bcl-2/Bcl-xL/Bcl-w inhibitor; a selective Bcl-xL inhibitor; a Bcl-xL/Bcl-w inhibitor); an Akt kinase specific inhibitor; or an MDM2 inhibitor.
  • methods comprise use of at least two senolytic agents wherein at least one senolytic agent and a second senolytic agent are each different and independently alter either one or both of a survival signaling pathway and an inflammatory pathway in a senescent cell.
  • Senolytic agents that may be used in the methods for treating or preventing a senescence-associated disease or disorder include small organic molecules.
  • Small organic molecules also called small molecules or small molecule compounds herein typically have molecular weights less than 105 daltons, less than 104 daltons, or less than 103 daltons.
  • a small molecule senolytic agent does not violate the following criteria more than once: (1 ) no more than 5 hydrogen bond donors (the total number of nitrogen-hydrogen and oxygen-hydrogen bonds); (2) not more than 10 hydrogen bond acceptors (all nitrogen or oxygen atoms); (3) a molecular mass less than 500 daltons; (4) an octanol-water partition coefficient log P not greater than 5.
  • the senolytic agent may be an MDM2 inhibitor.
  • An MDM2 (murine double minute 2) inhibitor that may be used in the methods for selectively killing senescent cells and treating or preventing (i.e., reducing or decreasing the likelihood of occurrence or development of) a senescence-associated disease or disorder may be a small molecule compound that belongs to any one of the following classes of compounds, for example, a cis-imidazoline compound, a spiro- oxindole compound, a benzodiazepine compound, a piperidinone compound, a tryptamine compound, and CGM097, and related analogs.
  • the MDM2 inhibitor is also capable of binding to and inhibiting an activity of MDMX (murine double minute X, which is also known as HDMX in humans).
  • MDMX murine double minute X
  • HDM2 human double minute 2
  • the compounds described herein as MDM2 inhibitors also inhibit binding of HDM2 to one or more of its ligands.
  • TRIM28/KAP1 -ERBB4-MDM2 complex that links growth factor and DNA damage response pathways; mediates ubiquitination and subsequent proteasome degradation of DYRK2 in the nucleus; ubiquitinates IGF1 R and SNAI1 and promotes them to proteasomal degradation.
  • MDM2 has also been reported to induce mono-ubiquitination of the transcription factor F0X04 (see, e.g., Brenkman et al., PLOS One 3(7):e2819, doi:10.1371/journal. pone.0002819).
  • the MDM2 inhibitors described herein may disrupt the interaction between MDM2 and any one or more of the aforementioned cellular components.
  • a compound useful for the methods described herein is a cis-imidazoline small molecule inhibitor.
  • Cis-imidazoline compounds include those called nutlins in the art. Similar to other MDM2 inhibitors described herein, nutlins are cis-imidazoline small molecule inhibitors of the interaction between MDM2 and p53
  • the methods described herein comprise use of a nutlin compound called Nutlin-1 ; or a nutlin compound called Nutlin-2; or a Nutlin compound called Nutlin-3 (see CAS Registry No. 675576-98-4 and No. 548472-68-0).
  • Nutlin-3a The active enantiomer of Nutlin-3 (4-[[4S,5R)-4,5-bis(4-chlorophenyl)-4,5-dihydro-2-[4-methoxy-2-(- 1 -methylethoxy)phenyl]-1 H-imidazol-1 -yl]carbonyl]-2-piperazinone) is called Nutlin-3a in the art.
  • the methods described herein comprise use of Nutlin- 3a for selectively killing senescent cells.
  • Another exemplary cis-imidazoline small molecule compound useful for selectively killing senescent cells is RG-71 12 (Roche) (CAS No: 939981 -39-2; IUPAC name: ((4S,5R)-2-(4-(tert-butyl)-2-ethoxyphenyl)-4,5-bis(4-chlorophenyl)-4,5-di- methyl-4,5-dihydro-1 H-imidazol-1 -yl)(4-(3-(methylsulfonyl)propyl)piperazin- -1 - yl)methanone.
  • the MDM2 inhibitor is a cis-imidazoline compound called RG7338 (Roche) (IPUAC Name: 4-((2R,3S,4R,5S)-3-(3-chloro-2- fluorophenyl)-4-(4-chloro-2-fluorophenyl) ⁇ 4-cyano-5-neopentylpyrrolidine-2- carboxamido)-3-methoxybenzoic acid) (CAS 1229705-06-9.
  • Yet another exemplary nutlin compound is RO5503781 .
  • Other potent cis-imidazoline small molecule compounds include dihydroimidazothiazole compounds (e.g., DS-3032b; Daiichi Sankyo).
  • a cis-imidazoline compound that may be used in the methods described herein is a dihydroimidazothiazole compound.
  • the MDM2 small molecule inhibitor is a spiro-oxindole compound. See, for example, MDM2 inhibitors called in the art MI-63, MI-126; MI-122, MI-142, MI-147, MI-18, MI-219, MI-220, MI-221 , and MI-773.
  • Another specific spiro-oxindole compound is 3-(4-chlorophenyl)-3-((1 -(hydroxymethyl)cyclopropyl)methoxy)-2-(4-nitrobe- nzyl)isoindolin-1 -one.
  • Another compound is called MI888.
  • the MDM2 small molecule inhibitor that may be used in the methods described herein is a benzodiazepinedione.
  • Benzodiazepinedione compounds that may be used in the methods described herein include 1 ,4-benzodiazepin-2,5-dione compounds.
  • Examples of benzodiazepinedione compounds include 5-[(3S)-3-(4-chlorophenyl)-4-[(R)-1 -(4-chlorophenyl)ethyl]-2,5-dioxo- 7-ph- enyl-1 ,4-diazepin-1 -yl]valeric acid and 5-[(3S)-7-(2-bromophenyl)-3-(4- chlorophenyl)-4-[(R)-1 -(4-chlorophenyl)eth- yl]-2,5-dioxo-1 ,4-diazepin-1 -yl]valeric acid.
  • TDP521252 IUPAC Name: 5-[(3S)-3-(4-chlorophenyl)-4-[(1 R)-1 -(4-chlorophenyl)ethyl]-7-ethynyl-2,5- -dioxo-3H-1 ,4- benzodiazepin-1 -yl]pentanoic acid
  • TDP665759 IUPAC Name: (3S)-4-[(1 R)-1 -(2- amino-4-chlorophenyl)ethyl]-3-(4-chlorophenyl)-7- iodo-1 -[3-(4-methylpiperazin-1 - yl)propyl]-3H-1 ,4-benzodiazepine-2,5-dione).
  • the MDM2 small molecule inhibitor is a terphenyl (see, e.g., Yin et al., Angew Chem Int Ed Engl 2005; 44:2704-707; Chen et al., Mol Cancer Ther 2005; 4:1019-25).
  • the MDM2 inhibitor that may be used in the methods described herein is a quilinol (see, e.g., Lu et al., J Med Chem 2006; 49:3759-62).
  • the MDM2 inhibitor is a chalcone (see, e.g., Stoll et al., Biochemistry 2001 ; 40:336-44).
  • the MDM2 inhibitor is a sulfonamide (e.g., NSC279287) (see, e.g., Galatin et al., J Med Chem 2004; 47:4163-65).
  • a compound that may be used in the methods described herein is a tryptamine, such as serdemetan (JNJ-26854165; chemical name: N1 -(2-(1 H-indol-3-yl)ethyl)-N4-(pyridine-4- yl)benzene-1 ,4-diamine; CAS No. 881202-45-5) (Johnson & Johnson, New Brunswick, N.J.).
  • Serdemetan is a tryptamine derivative that activates p53 and acts as a HDM2.
  • the MDM2 inhibitor is a piperidinone compound.
  • An example of a potent MDM2 piperidinone inhibitor is AM-8553 ( ⁇ (3R,5R,6S)-5-(3-Chlorophenyl)-6-(4- chlorophenyl)-1 -[(2S,3S)-2-hydroxy-3- -pentanyl]-3-methyl-2-oxo-3-piperidinyl ⁇ acetic acid; CAS No. 1352064-70-0) (Amgen, Thousand Oaks, Calif.).
  • an MDM2 inhibitor that may be used in the methods described herein is a piperidine (Merck, Whitehouse Station, N.J.).
  • an MDM2 inhibitor that may be used in the methods is an imidazole-indole compound (Novartis) (see, e.g., Int'l Patent Appl. Publ. No. WO 2008/1 19741 ).
  • Examples of compounds that bind to MDM2 and to MDMX and that may be used in the methods described herein include RO-2443 and RO-5963 ((Z)-2-(4- ((6-Chloro-7-methyl-1 H-indol-3-yl)methylene)-2,5-dioxoimidazoli- din-1 -yl)-2-(3,4- difluorophenyl)-N-(1 ,3-dihydroxypropan-2-yl)acetamide).
  • RO-2443 and RO-5963 ((Z)-2-(4- ((6-Chloro-7-methyl-1 H-indol-3-yl)methylene)-2,5-dioxoimidazoli- din-1 -yl)-2-(3,4- difluorophenyl)-N-(1 ,3-dihydroxypropan-2-yl)acetamide).
  • an MDM2 inhibitor referred to in the art as CGM097 may be used in the methods described herein for selectively killing senescent cells and for treating a senescence-associated disease or disorder.
  • the senolytic agent may be an inhibitor of one or more proteins in the BCL-2 family.
  • the at least one senolytic agent is selected from an inhibitor of one or more BCL-2 anti-apoptotic protein family members wherein the inhibitor inhibits at least BCL-xL.
  • Inhibitors of BCL-2 anti- apoptotic family of proteins alter at least a cell survival pathway. Apoptosis activation may occur via an extrinsic pathway triggered by the activation of cell surface death receptors or an intrinsic pathway triggered by developmental cues and diverse intracellular stresses.
  • BCL-2 anti-apoptotic proteins having BH1 -BH4 domains
  • BCL-2 anti-apoptotic proteins having BH1 -BH4 domains
  • BCL-2 anti-apoptotic proteins having BH1 -BH4 domains
  • BCL-2 anti-apoptotic proteins having BH1 , BH2, and BH3 domains BAX, BAK, and BOK
  • pro-apoptotic BH3-only proteins BIK, BAD, BID, BIM, BMF, HRK, NOXA, and PUMA.
  • BCL-2 anti- apoptotic proteins block activation of pro-apoptotic multi-domain proteins BAX and BAK.
  • a BCL-2 family member that is inhibited by the agents described herein is a pro-survival (anti-apoptotic) family member.
  • the senolytic agents used in the methods described herein inhibit one or more functions of the BCL-2 anti-apoptotic protein, BCL-xL (which may also be written herein and in the art as Bcl-xL, BCL-XL, Bcl-xl, or Bcl-XL).
  • BCL-xL which may also be written herein and in the art as Bcl-xL, BCL-XL, Bcl-xl, or Bcl-XL.
  • the inhibitor in addition to inhibiting BCL-xL function, may also interact with and/or inhibit one or more functions of BCL-2 (i.e., BCL-xL/BCL-2 inhibitors).
  • BCL-2 i.e., BCL-xL/BCL-2 inhibitors
  • senolytic agents used in the methods described herein are classified as inhibitors of each of BCL-xL and BCL-w (i.e., BCL-xL/BCL-w inhibitors).
  • senolytic agents used in the methods described herein that inhibit BCL-xL may also interact with and inhibit one or more functions of each of BCL-2 (i.e., the BCL-2 protein) and BCL-w (i.e., BCL-xL/BCL-2/BCL-w inhibitors), thereby causing selective killing of senescent cells.
  • BCL-2 anti-apoptotic protein inhibitor interferes with the interaction between the BCL-2 anti-apoptotic protein family member (which includes at least BCL-xL) and one or more ligands or receptors to which the BCL-2 anti-apoptotic protein family member would bind in the absence of the inhibitor.
  • an inhibitor of one or more BCL-2 anti-apoptotic protein family members wherein the inhibitor inhibits at least BCL-xL specifically binds only to one or more of BCL-xL, BCL-2, BCL-w and not to other Bcl-2 anti-apoptotic Bcl-2 family members, such as Mcl-1 and BCL2A1 .
  • the senolytic agent used in the methods described herein is a BCL-xL selective inhibitor and inhibits one or more functions of BCL-xL.
  • BCL-xL selective inhibitors do not inhibit the function of one or more other BCL-2 anti-apoptotic proteins in a biologically or statistically significant manner
  • BCL-xL may also be called BCL2L1 , BCL2-like 1 , BCLX, BCL2L, BCLxL, or BCL-X herein and in the art.
  • BCL-xL selective inhibitors alter (e.g., reduce, inhibit, decrease, suppress) one or more functions of BCL- xL but do not significantly inhibit one or more functions of other proteins in the BCL-2 anti-apoptotic protein family (e.g., BCL-2 or BCL-w).
  • a BCL-xL selective inhibitor interferes with the interaction between BCL-xL and one or more ligands or receptors to which BCL-xL would bind in the absence of the inhibitor.
  • a senolytic agent that inhibits one or more of the functions of BCL-xL selectively binds to human BCL-xL but not to other proteins in the BCL-2 family, which effects selective killing of senescent cells.
  • a BCL-xL inhibitor is a selective inhibitor, meaning, that it preferentially binds to BCL-xL over other anti-apoptotic BCL2 family members (e.g., BCL-2, MCL-1 , BCL-w, BCL-b, and BFL-1/A1 ).
  • a BCL-XL selective inhibitor exhibits at least a 5-fold, 10-fold, 50-fold, 100-fold, 1000- fold, 10000-fold, 20000-fold, or 30000-fold selectivity for binding a BCL-XL protein or nucleic acid over a BCL-2 protein or nucleic acid.
  • a BCL-xL selective inhibitor exhibits at least a 5-fold, 10-fold, 50-fold, 100-fold, 1000-fold, 10000- fold, 20000-fold, or 30000-fold selectivity for binding a BCL-xL protein or nucleic acid over a MCL-1 protein or nucleic acid. In certain embodiments, a BCL-xL selective inhibitor exhibits at least a 5-fold, 10-fold, 50-fold, 100-fold, 1000-fold, 10000-fold, 20000-fold, or 30000-fold selectivity for binding a BCL-xL protein or nucleic acid over a BCL-w protein or nucleic acid.
  • a BCL-xL selective inhibitor exhibits at least a 5-fold, 10-fold, 50-fold, 100-fold, 1000-fold, 10000-fold, 20000-fold, or 30000-fold selectivity for binding a BCL-XL protein or nucleic acid over a BCL-B protein or nucleic acid.
  • a BCL-XL selective inhibitor exhibits at least a 5-fold, 10-fold, 50-fold, 100-fold, 1000-fold, 10000-fold, 20000-fold, or 30000-fold selectivity for binding a BCL-xL protein or nucleic acid over an A1 protein or nucleic acid.
  • an inhibitor of one or more BCL-2 anti-apoptotic protein family members wherein the inhibitor inhibits at least BCL-xL e.g., a BCL-xL selective inhibitor
  • the inhibitor inhibits at least BCL-xL (e.g., a BCL-xL selective inhibitor) has no detectable binding to MCL-1 or to BCL2A1 .
  • binding affinity of a BCL-xL inhibitor may be determined using a competition fluorescence polarization assay in which a fluorescent BAK BH3 domain peptide is incubated with BCL-xL protein (or other BCL-2 family protein) in the presence or absence of increasing concentrations of the BCL-XL inhibitor.
  • the BCL-xL inhibitor is a small molecule compound that belongs to any one of the following classes of compounds, for example, a benzothiazole-hydrazone compound, aminopyridine compound, benzimidazole compound, tetrahydroquinoline compound, and phenoxyl compound and related analogs.
  • a BCL-xL selective inhibitor useful for the methods described herein is a benzothiazole-hydrazone small molecule inhibitor.
  • Benzothiazole-hydrazone compounds include WEHI-539 (5-[3-[4- (aminomethyl)phenoxy]propyl]-2-[(8E)-8-(1 ,3-benzothiazol-2-ylhyd- razinylidene)-6,7- dihydro-5H-naphthalen-2-yl]-1 ,3-thiazole-4-carboxylic acid), a BH3 peptide mimetic that selectively targets BCL-xL (see, e.g., Lessene et al., Nature Chemical Biology 9:390- 397 (2013)).
  • the methods described herein comprise use of WEHI-539 for selectively killing senescent cells.
  • the BCL-xL selective inhibitor is an aminopyridine compound.
  • An aminopyridine compound that may be used as a selective BCL-xL inhibitor is BXI-61 (3-[(9-amino-7-ethoxyacridin-3-yl)diazenyl]pyridine-2,6- diamine).
  • the methods described herein comprise use of BXI- 61 for selectively killing senescent cells.
  • the BCL-xL selective inhibitor that may be used in the methods described herein is a benzimidazole compound.
  • BCL-XL inhibitor An example of a benzimidazole compound that may be used as a selective BCL-XL inhibitor is BXI-72 (2'-(4-Hydroxyphenyl)-5-(4-methyl-1 -piperazinyl)-2,5'-bi(1 H- benzimidazole- ) trihydrochloride).
  • the methods described herein comprise use of BXI-72 for selectively killing senescent cells.
  • the BCL-xL selective inhibitor is a tetrahydroquinoline compound (see, e.g., U.S. Patent Publ. No. 2014-0005190).
  • a BCL-xL selective inhibitor is a phenoxyl compound.
  • An example of a phenoxyl compound that may be used as a selective BCL- xL inhibitor is 2[[3-(2,3-dichlorophenoxy) propyl]amino]ethanol (2,3-DCPE).
  • the methods described herein comprise use of 2,3-DCPE for selectively killing senescent cells.
  • an inhibitor of a Bcl-2 anti-apoptotic family member that inhibits at least BCL-xL is described in U.S. Pat. No. 8,232,273.
  • the inhibitor is a BCL-xL selective inhibitor called A-1 155463 (see, e.g., Tao et al., ACS Med. Chem. Lett., 2014, 5(10):.
  • the senolytic agent is a compound that induces degradation of a Bcl-2 anti-apoptotic family member such as those described above in section (l)(a) and section (l)(b).
  • a senolytic agent of interest inhibits other BCL-2 anti-apoptotic family members in addition to BCL-xL.
  • methods described herein comprise use of BCL-xL/BCL-2 inhibitors, BCL-xL/BCL-2/BCL-w inhibitors, and BCL-xL/BCL-w inhibitors and analogs thereof.
  • the inhibitors include compounds that inhibit BCL-2 and BCL-xL, which inhibitors may also inhibit BCL-w.
  • inhibitors examples include ABT-263 (4-[4-[[2-(4- chlorophenyl)-5,5-dimethylcyclohexen-1 -yl]methyl]piperazin-1 - -yl]-N-[4-[[(2R)-4- morpholin-4-yl-1 -phenylsulfanylbutan-2-yl]amino]-3-(tri- fluoromethylsulfonyl)phenyl]sulfonylbenzamide or IUPAC, (Ft)-4-(4-((4'-chloro-4,4- dimethyl-3,4,5,6-tetrahydro-[1 ,1’-biphenyl]-2-yl- )methyl)piperazin-1 -yl)-N-((4-((4- morpholino-1 -(phenylthio)butan-2-yl)amin- o)-3-
  • the BCL-2 anti-apoptotic protein inhibitor is a quinazoline sulfonamide compound.
  • the BCL-2 anti-apoptotic protein inhibitor is a small molecule compound as described in Zhou et al. , J. Med.
  • the BCL-2 anti-apoptotic protein inhibitor is a BCL-2/BCL-xL inhibitor such as BM-1074; BM-1 197; N-acylsufonamide compounds.
  • the BCL-2 anti- apoptotic protein inhibitor is a small molecule macrocyclic compound.
  • the BCL-2 anti-apoptotic protein inhibitor is an isoxazolidine compound.
  • the senolytic agent is a compound that is an inhibitor of Bcl-2, Bcl-w, and Bcl-xL, such as ABT-263 or ABT-737.
  • the senolytic agent is a compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, or prodrug thereof as illustrated below, which depicts the structure of ABT-263.
  • ABT-263 is also known as Navitoclax in the art.
  • the senolytic agent is an Akt Kinase inhibitor.
  • a senolytic agent can be a small molecule compound and analogs thereof that inhibits Akt.
  • the senolytic agent is a compound that selectively inhibits Akt1 , Akt2, and Akt3, relative to other protein kinases.
  • Akt inhibitors (which may also be called Akt kinase inhibitors or AKT kinase inhibitors) can be divided into six major classes based on their mechanisms of action. Akt is also called protein kinase B (PKB) in the art.
  • the first class contains ATP competitive inhibitors of Akt and includes compounds such as CCT 128930 and GDC-0068, which inhibit Akt2 and Akt1 .
  • This category also includes the pan-Akt kinase inhibitors such as GSK21 10183 (afuresertib), GSK690693, and AT7867.
  • the second class contains lipid-based Akt inhibitors that act by inhibiting the generation of PIP3 by PI3K. This mechanism is employed by phosphatidylinositol analogs such as
  • This category also includes compounds such as Perifosine (KRX-0401 ) (Aeterna).
  • the third class contains a group of compounds called pseudosubstrate inhibitors. These include compounds such as AKTide-2 T and FOX03 hybrid.
  • the fourth class consists of allosteric inhibitors of AKT kinase domain, and include compounds such as MK-2206 (8-[4-(1 -aminocyclobutyl)phenyl]-9-phenyl-2H- [1 ,2,4]triazolo[3,4-f][1 ,6]n- aphthyridin-3-one; dihydrochloride) (Merck & Co.).
  • the fifth class consists of antibodies and include molecules such as GST-anti-Akt1 -MTS.
  • the last class comprises compounds that interact with the PH domain of Akt, and includes Triciribine and PX-316.
  • Other compounds described in the art that act as AKT inhibitors include, for example, GSK-2141795 (GlaxoSmithKline), VQD-002, miltefosine,
  • At least one senolytic agent may be administered with at least one other senolytic agent, which two or more senolytic agents act additively or synergistically to selectively kill senescent cells.
  • methods are provided for using a senolytic agent wherein the senolytic agent alters either a cell survival signaling pathway or an inflammatory pathway or alters both the cell survival signaling pathway and the inflammatory pathway in a senescent cell.
  • methods comprise use of at least two senolytic agents wherein at least one senolytic agent and a second senolytic agent are each different and independently alter either one or both of a survival signaling pathway and an inflammatory pathway in a senescent cell.
  • the adjectives, first, second, third, and such, in this context are used for convenience only and are not to be construed as describing order or administration, preference, or level of senolytic activity or other parameter unless expressly described otherwise.
  • each senolytic agent is a small molecule.
  • the small molecule compounds described herein as senolytic agents include physiologically acceptable salts (i.e., pharmaceutically acceptable salts), hydrates, solvates, polymorphs, metabolites, and prodrugs of the senolytic agents. Further information on metabolism may be obtained from The Pharmacological Basis of Therapeutics, 9th Edition, McGraw-Hill (1996). Metabolites of the compounds disclosed herein can be identified either by administration of compounds to a host and analysis of tissue samples from the host, or by incubation of compounds with hepatic cells in vitro and analysis of the resulting compounds. Both methods are well known in the art.
  • the compounds described herein may generally be used as the free acid or free base. Alternatively, the compounds may be used in the form of acid or base addition salts. Acid addition salts of the free base amino compounds may be prepared according to methods well known in the art, and may be formed from organic and inorganic acids. Suitable organic acids include (but are not limited to) maleic, fumaric, benzoic, ascorbic, succinic, methanesulfonic, acetic, oxalic, propionic, tartaric, salicylic, citric, gluconic, lactic, mandelic, cinnamic, aspartic, stearic, palmitic, glycolic, glutamic, malonic, and benzenesulfonic acids.
  • Suitable inorganic acids include (but are not limited to) hydrochloric, hydrobromic, sulfuric, phosphoric, and nitric acids.
  • Base addition salts of the free acid compounds of the compounds described herein may also be prepared by methods well known in the art, and may be formed from organic and inorganic bases. Additional salts include those in which the counterion is a cation.
  • Suitable inorganic bases included include (but are not limited to) the hydroxide or other salt of sodium, potassium, lithium, ammonium, calcium, barium, magnesium, iron, zinc, copper, manganese, aluminum, and the like, and organic bases such as substituted ammonium salts (for example, dibenzylammonium, benzylammonium, 2- hydroxyethylammonium).
  • Further salts include those in which the counterion is an anion, such as adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate,
  • an anion such as adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate,
  • Compounds may sometimes be depicted as an anionic species.
  • the compounds described herein can exist in the fully protonated form, or in the form of a salt such as sodium, potassium, ammonium or in combination with any inorganic base as described above.
  • each anionic species may independently exist as either the protonated species or as the salt species.
  • the compounds described herein exist as the sodium salt.
  • the compounds described herein exist as the potassium salt.
  • solvates refers to an aggregate that comprises one or more molecules of any of the disclosed compounds with one or more molecules of solvent.
  • the solvent may be water, in which case the solvate may be a hydrate.
  • the solvent may be an organic solvent.
  • the presently disclosed compounds may exist as a hydrate, including a monohydrate, dihydrate, hemihydrate, sesquihydrate, trihydrate, tetrahydrate and the like, as well as the corresponding solvated forms. Certain embodiments of the compounds may be true solvates, while in other instances, some embodiments of the compounds may merely retain adventitious water or be a mixture of water plus some adventitious solvent.
  • the compounds used in the methods described herein may be made according to organic synthesis techniques known to those skilled in this art, starting from commercially available chemicals and/or from compounds described in the chemical literature. Specific and analogous reactants may also be identified through the indices of known chemicals prepared by the Chemical Abstract Service of the American Chemical Society, which are available in most public and university libraries, as well as through on-line databases (the American Chemical Society, Washington, D.C., may be contacted for more details). Chemicals that are known but not
  • the present disclosure also provides pharmaceutical compositions.
  • the pharmaceutical compositions comprise a compound of Formula (I), a compound of Formula (II), a senolytic agent or a combination thereof, as an active ingredient and at least one pharmaceutically acceptable excipient.
  • the pharmaceutically acceptable excipient may be a diluent, a binder, a filler, a buffering agent, a pH modifying agent, a disintegrant, a dispersant, a preservative, a lubricant, taste-masking agent, a flavoring agent, or a coloring agent.
  • the amount and types of excipients utilized to form pharmaceutical compositions may be selected according to known principles of pharmaceutical science.
  • the excipient may be a diluent.
  • the diluent may be compressible (i.e., plastically deformable) or abrasively brittle.
  • suitable compressible diluents include microcrystalline cellulose (MCC), cellulose derivatives, cellulose powder, cellulose esters (i.e., acetate and butyrate mixed esters), ethyl cellulose, methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose, corn starch, phosphated corn starch, pregelatinized corn starch, rice starch, potato starch, tapioca starch, starch-lactose, starch-calcium carbonate, sodium starch glycolate, glucose, fructose, lactose, lactose monohydrate, sucrose, xylose, lactitol, mannitol, malitol, sorbitol, xylito
  • the excipient may be a binder.
  • Suitable binders include, but are not limited to, starches, pregelatinized starches, gelatin, polyvinylpyrrolidone, cellulose, methylcellulose, sodium carboxymethylcellulose, ethylcellulose, polyacrylamides, polyvinyloxoazolidone, polyvinylalcohols, C12-C18 fatty acid alcohol, polyethylene glycol, polyols, saccharides, oligosaccharides, polypeptides, oligopeptides, and combinations thereof.
  • the excipient may be a filler.
  • suitable fillers include, but are not limited to, carbohydrates, inorganic compounds, and polyvinylpyrrolidone.
  • the filler may be calcium sulfate, both di- and tri-basic, starch, calcium carbonate, magnesium carbonate, microcrystalline cellulose, dibasic calcium phosphate, magnesium carbonate, magnesium oxide, calcium silicate, talc, modified starches, lactose, sucrose, mannitol, or sorbitol.
  • the excipient may be a buffering agent.
  • buffering agents include, but are not limited to, phosphates, carbonates, citrates, tris buffers, and buffered saline salts (e.g., Tris buffered saline or phosphate buffered saline).
  • the excipient may be a pH modifier.
  • the pH modifying agent may be sodium carbonate, sodium bicarbonate, sodium citrate, citric acid, or phosphoric acid.
  • the excipient may be a disintegrant.
  • the disintegrant may be non-effervescent or effervescent.
  • Suitable examples of non- effervescent disintegrants include, but are not limited to, starches such as corn starch, potato starch, pregelatinized and modified starches thereof, sweeteners, clays, such as bentonite, micro-crystalline cellulose, alginates, sodium starch glycolate, gums such as agar, guar, locust bean, karaya, pecitin, and tragacanth.
  • suitable effervescent disintegrants include sodium bicarbonate in combination with citric acid and sodium bicarbonate in combination with tartaric acid.
  • the excipient may be a dispersant or dispersing enhancing agent.
  • Suitable dispersants may include, but are not limited to, starch, alginic acid, polyvinylpyrrolidones, guar gum, kaolin, bentonite, purified wood cellulose, sodium starch glycolate, isoamorphous silicate, and microcrystalline cellulose.
  • the excipient may be a preservative.
  • suitable preservatives include antioxidants, such as BHA, BHT, vitamin A, vitamin C, vitamin E, or retinyl palmitate, citric acid, sodium citrate; chelators such as EDTA or EGTA; and antimicrobials, such as parabens, chlorobutanol, or phenol.
  • the excipient may be a lubricant.
  • suitable lubricants include minerals such as talc or silica; and fats such as vegetable stearin, magnesium stearate or stearic acid.
  • the excipient may be a taste-masking agent.
  • Taste-masking materials include cellulose ethers; polyethylene glycols; polyvinyl alcohol; polyvinyl alcohol and polyethylene glycol copolymers; monoglycerides or triglycerides; acrylic polymers; mixtures of acrylic polymers with cellulose ethers;
  • the excipient may be a flavoring agent.
  • Flavoring agents may be chosen from synthetic flavor oils and flavoring aromatics and/or natural oils, extracts from plants, leaves, flowers, fruits, and combinations thereof.
  • the excipient may be a coloring agent.
  • Suitable color additives include, but are not limited to, food, drug and cosmetic colors (FD&C), drug and cosmetic colors (D&C), or external drug and cosmetic colors (Ext. D&C).
  • the weight fraction of the excipient or combination of excipients in the composition may be about 99% or less, about 97% or less, about 95% or less, about 90% or less, about 85% or less, about 80% or less, about 75% or less, about 70% or less, about 65% or less, about 60% or less, about 55% or less, about 50% or less, about 45% or less, about 40% or less, about 35% or less, about 30% or less, about 25% or less, about 20% or less, about 15% or less, about 10% or less, about 5% or less, about 2%, or about 1 % or less of the total weight of the composition.
  • compositions can be formulated into various dosage forms and administered by a number of different means that will deliver a therapeutically effective amount of the active ingredient.
  • Such compositions can be administered orally, parenterally, or topically in dosage unit formulations containing conventional nontoxic pharmaceutically acceptable carriers, adjuvants, and vehicles as desired.
  • Topical administration may also involve the use of transdermal administration such as transdermal patches or iontophoresis devices.
  • parenteral as used herein includes subcutaneous, intravenous, intramuscular, or intrasternal injection, or infusion techniques. Formulation of drugs is discussed in, for example, Gennaro, A. R., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa. (18th ed, 1995), and Liberman, H. A.
  • a composition may be a food supplement or a composition may be a cosmetic.
  • Solid dosage forms for oral administration include capsules, tablets, caplets, pills, powders, pellets, and granules.
  • the active ingredient is ordinarily combined with one or more pharmaceutically acceptable excipients, examples of which are detailed above.
  • Oral preparations may also be administered as aqueous suspensions, elixirs, or syrups.
  • the active ingredient may be combined with various sweetening or flavoring agents, coloring agents, and, if so desired, emulsifying and/or suspending agents, as well as diluents such as water, ethanol, glycerin, and combinations thereof.
  • the preparation may be an aqueous or an oil-based solution.
  • Aqueous solutions may include a sterile diluent such as water, saline solution, a pharmaceutically acceptable polyol such as glycerol, propylene glycol, or other synthetic solvents; an antibacterial and/or antifungal agent such as benzyl alcohol, methyl paraben, chlorobutanol, phenol, thimerosal, and the like; an antioxidant such as ascorbic acid or sodium bisulfite; a chelating agent such as
  • etheylenediaminetetraacetic acid etheylenediaminetetraacetic acid
  • a buffer such as acetate, citrate, or phosphate
  • an agent for the adjustment of tonicity such as sodium chloride, dextrose, or a polyalcohol such as mannitol or sorbitol.
  • the pH of the aqueous solution may be adjusted with acids or bases such as hydrochloric acid or sodium hydroxide.
  • Oil-based solutions or suspensions may further comprise sesame, peanut, olive oil, or mineral oil.
  • compositions may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carried, for example water for injections, immediately prior to use.
  • sterile liquid carried, for example water for injections, immediately prior to use.
  • Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets.
  • compositions adapted for topical administration may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils.
  • the pharmaceutical composition is applied as a topical ointment or cream.
  • the active ingredient may be employed with either a paraffinic or a water-miscible ointment base.
  • the active ingredient may be formulated in a cream with an oil-in-water cream base or a water-in-oil base.
  • Pharmaceutical compositions adapted for topical administration to the eye include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent.
  • Pharmaceutical compositions adapted for topical administration in the mouth include lozenges, pastilles and mouth washes. Transmucosal administration may be accomplished through the use of nasal sprays, aerosol sprays, tablets, or suppositories, and transdermal administration may be via ointments, salves, gels, patches, or creams as generally known in the art.
  • a composition comprising a compound of Formula (I), a compound of Formula (II), a senolytic agent or a combination thereof, is encapsulated in a suitable vehicle to either aid in the delivery of the compound to target cells, to increase the stability of the composition, or to minimize potential toxicity of the composition.
  • a suitable vehicle is suitable for delivering a composition of the present invention.
  • suitable structured fluid delivery systems may include nanoparticles, liposomes, microemulsions, micelles, dendrimers and other phospholipid-containing systems. Methods of incorporating compositions into delivery vehicles are known in the art.
  • a liposome delivery vehicle may be utilized.
  • Liposomes depending upon the embodiment, are suitable for delivery a compound of Formula (I), a compound of Formula (II), a senolytic agent or a combination thereof, in view of their structural and chemical properties.
  • liposomes are spherical vesicles with a phospholipid bilayer membrane.
  • the lipid bilayer of a liposome may fuse with other bilayers (e.g., the cell membrane), thus delivering the contents of the liposome to cells.
  • a compound of Formula (I), a compound of Formula (II), a senolytic agent or a combination thereof may be selectively delivered to a cell by encapsulation in a liposome that fuses with the targeted cell’s membrane.
  • Liposomes may be comprised of a variety of different types of phosolipids having varying hydrocarbon chain lengths. Phospholipids generally comprise two fatty acids linked through glycerol phosphate to one of a variety of polar groups.
  • Suitable phospholids include phosphatidic acid (PA), phosphatidylserine (PS), phosphatidylinositol (PI), phosphatidylglycerol (PG), diphosphatidylglycerol (DPG), phosphatidylcholine (PC), and phosphatidylethanolamine (PE).
  • PA phosphatidic acid
  • PS phosphatidylserine
  • PI phosphatidylinositol
  • PG phosphatidylglycerol
  • DPG diphosphatidylglycerol
  • PC phosphatidylcholine
  • PE phosphatidylethanolamine
  • the fatty acid chains comprising the phospholipids may range from about 6 to about 26 carbon atoms in length, and the lipid chains may be saturated or unsaturated.
  • Suitable fatty acid chains include (common name presented in parentheses) n-dodecanoate (laurate), n- tretradecanoate (myristate), n-hexadecanoate (palmitate), n-octadecanoate (stearate), n-eicosanoate (arachidate), n-docosanoate (behenate), n-tetracosanoate (lignocerate), cis-9-hexadecenoate (palmitoleate), cis-9-octadecanoate (oleate), cis,cis-9,12- octadecandienoate (linoleate), all cis-9, 12, 15-octadecatrienoate (linolenate), and all cis-5,8,1 1 ,14-eicosatetraenoate (arachidonate).
  • the two fatty acid chains of a phospholipid may be identical or different.
  • Acceptable phospholipids include dioleoyl PS, dioleoyl PC, distearoyl PS, distearoyl PC, dimyristoyl PS, dimyristoyl PC, dipalmitoyl PG, stearoyl, oleoyl PS, palmitoyl, linolenyl PS, and the like.
  • the phospholipids may come from any natural source, and, as such, may comprise a mixture of phospholipids.
  • egg yolk is rich in PC, PG, and PE
  • soy beans contains PC, PE, PI, and PA
  • animal brain or spinal cord is enriched in PS.
  • Phospholipids may come from synthetic sources too. Mixtures of phospholipids having a varied ratio of individual phospholipids may be used. Mixtures of different phospholipids may result in liposome compositions having advantageous activity or stability of activity properties.
  • the above mentioned phospholipids may be mixed, in optimal ratios with cationic lipids, such as N-(1 -(2,3-dioleolyoxy)propyl)-N,N,N- trimethyl ammonium chloride, 1 ,1’-dioctadecyl-3,3,3’,3’-tetramethylindocarbocyanine perchloarate, 3,3’-deheptyloxacarbocyanine iodide, 1 ,1’-dedodecyl-3,3,3’,3’- tetramethylindocarbocyanine perchloarate, 1 ,1’-dioleyl-3,3,3’,3’-tetramethylindo carbocyanine methanesulfonate, N-4-(delinoleylaminostyryl)-N-methylpyridinium iodide, or 1 ,1 ,-dilinoleyl-3,3,3’
  • Liposomes may optionally comprise sphingolipids, in which spingosine is the structural counterpart of glycerol and one of the one fatty acids of a phosphoglyceride, or cholesterol, a major component of animal cell membranes.
  • Liposomes may optionally contain pegylated lipids, which are lipids covalently linked to polymers of polyethylene glycol (PEG). PEGs may range in size from about 500 to about 10,000 daltons.
  • Liposomes may further comprise a suitable solvent.
  • the solvent may be an organic solvent or an inorganic solvent.
  • Suitable solvents include, but are not limited to, dimethylsulfoxide (DMSO), methylpyrrolidone, N-methylpyrrolidone, acetronitrile, alcohols, dimethylformamide, tetrahydrofuran, or combinations thereof.
  • Liposomes carrying a compound of Formula (I) or a compound of Formula (II) may be prepared by any known method of preparing liposomes for drug delivery, such as, for example, detailed in U.S. Pat. Nos. 4,241 ,046, 4,394,448, 4,529,561 , 4,755,388, 4,828,837, 4,925,661 , 4,954,345, 4,957,735, 5,043,164, 5,064,655, 5,077,21 1 and 5,264,618, the disclosures of which are hereby incorporated by reference in their entirety.
  • liposomes may be prepared by sonicating lipids in an aqueous solution, solvent injection, lipid hydration, reverse evaporation, or freeze drying by repeated freezing and thawing.
  • the liposomes are formed by sonication.
  • the liposomes may be multilamellar, which have many layers like an onion, or unilamellar.
  • the liposomes may be large or small. Continued high-shear sonication tends to form smaller unilamellar lipsomes.
  • liposome formation may be varied. These parameters include, but are not limited to, temperature, pH, concentration of methionine compound, concentration and composition of lipid, concentration of multivalent cations, rate of mixing, presence of and concentration of solvent.
  • a composition of the invention may be delivered to a cell as a microemulsion.
  • Microemulsions are generally clear, thermodynamically stable solutions comprising an aqueous solution, a surfactant, and “oil.”
  • the "oil” in this case, is the supercritical fluid phase.
  • the surfactant rests at the oil-water interface. Any of a variety of surfactants are suitable for use in microemulsion formulations including those described herein or otherwise known in the art.
  • the aqueous microdomains suitable for use in the invention generally will have
  • microemulsions can and will have a multitude of different microscopic structures including sphere, rod, or disc shaped aggregates.
  • the structure may be micelles, which are the simplest microemulsion structures that are generally spherical or cylindrical objects. Micelles are like drops of oil in water, and reverse micelles are like drops of water in oil.
  • the microemulsion structure is the lamellae. It comprises consecutive layers of water and oil separated by layers of surfactant. The“oil” of microemulsions optimally comprises phospholipids.
  • any of the phospholipids detailed above for liposomes are suitable for embodiments directed to microemulsions.
  • the compound of Formula (I), compound of Formula (II), senolytic agent or a combination thereof may be encapsulated in a microemulsion by any method generally known in the art.
  • composition further comprises at least one or more anticancer therapeutics.
  • a chemotherapeutic agent refers to a chemical compound that is useful in the treatment of cancer.
  • the compound may be a cytotoxic agent that affects rapidly dividing cells in general, or it may be a targeted therapeutic agent that affects the deregulated proteins of cancer cells.
  • the chemotherapeutic agent may be an alkylating agent, an anti-metabolite, an anti-tumor antibiotic, an anti-cytoskeletal agent, a topoisomerase inhibitor, an anti-hormonal agent, a targeted therapeutic agent, a photodynamic therapeutic agent, or a combination thereof.
  • Non-limiting examples of suitable alkylating agents include altretamine, benzodopa, busulfan, carboplatin, carboquone, carmustine (BCNU), chlorambucil, chlornaphazine, cholophosphamide, chlorozotocin, cisplatin, cyclosphosphamide, dacarbazine (DTIC), estramustine, fotemustine, ifosfamide, improsulfan, lipoplatin, lomustine (CCNU), mafosfamide, mannosulfan, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, meturedopa, mustine (mechlorethamine), mitobronitol, nimustine, novembichin, oxaliplatin, phenesterine, piposulfan, prednimustine, ranimustine, satraplatin, semustine, temozolomide,
  • Suitable anti-metabolites include, but are not limited to aminopterin, ancitabine, azacitidine, 8-azaguanine, 6-azauridine, capecitabine, carmofur (1 - hexylcarbomoyl-5-fluorouracil), cladribine, clofarabine, cytarabine (cytosine arabinoside (Ara-C)), decitabine, denopterin, dideoxyuridine, doxifluridine, enocitabine, floxuridine, fludarabine, 5-fluorouracil, gemcetabine, hydroxyurea (hydroxycarbamide), leucovorin (folinic acid), 6-mercaptopurine, methotrexate, nafoxidine, nelarabine, oblimersen, pemetrexed, pteropterin, raltitrexed, tegofur, tiazofurin, thiamiprine, tioguan
  • Non-limiting examples of suitable anti-tumor antibiotics include aclacinomysin, aclarubicin, actinomycins, adriamycin, aurostatin (for example, monomethyl auristatin E), authramycin, azaserine, bleomycins, cactinomycin, calicheamicin, carabicin, caminomycin, carzinophilin, chromomycins, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin, epirubicin, epoxomicin, esorubicin, idarubicin, marcellomycin, mitomycins, mithramycin, mycophenolic acid, nogalamycin, olivomycins, peplomycin, plicamycin, potfiromycin, puromycin, quelamycin, rodorubicin, sparsomycin
  • Non-limiting examples of suitable anti-cytoskeletal agents include cabazitaxel, colchicines, demecolcine, docetaxel, epothilones, ixabepilone, macromycin, omacetaxine mepesuccinate, ortataxel, paclitaxel (for example, DHA-paclitaxel), taxane, tesetaxel, vinblastine, vincristine, vindesine, and vinorelbine.
  • Suitable topoisomerase inhibitors include, but are not limited to, amsacrine, etoposide (VP-16), irinotecan, mitoxantrone, RFS 2000, teniposide, and topotecan.
  • Non-limiting examples of suitable anti-hormonal agents such as aminoglutethimide, antiestrogen, aromatase inhibiting 4(5)-imidazoles, bicalutamide, finasteride, flutamide, fluvestrant, goserelin, 4-hydroxytamoxifen, keoxifene, leuprolide, LY1 17018, mitotane, nilutamide, onapristone, raloxifene, tamoxifen, toremifene, and trilostane.
  • suitable anti-hormonal agents such as aminoglutethimide, antiestrogen, aromatase inhibiting 4(5)-imidazoles, bicalutamide, finasteride, flutamide, fluvestrant, goserelin, 4-hydroxytamoxifen, keoxifene, leuprolide, LY1 17018, mitotane, nilutamide, onapristone, raloxifene, t
  • targeted therapeutic agents include, without limit, monoclonal antibodies such as alemtuzumab, cartumaxomab, edrecolomab, epratuzumab, gemtuzumab, gemtuzumab ozogamicin, glembatumumab vedotin, ibritumomab tiuxetan, reditux, rituximab, tositumomab, and trastuzumab; protein kinase inhibitors such as bevacizumab, cetuximab, crizonib, dasatinib, erlotinib, gefitinib, imatinib, lapatinib, mubritinib, nilotinib, panitumumab, pazopanib, sorafenib, sunitinib, toceranib, and vandetanib;
  • monoclonal antibodies such as alem
  • angiogeneisis inhibitors such as angiostatin, bevacizumab, denileukin diftitox, endostatin, everolimus, genistein, interferon alpha, interleukin-2, interleukin-12, pazopanib, pegaptanib, ranibizumab, rapamycin (sirolimus), temsirolimus, and thalidomide; and growth inhibitory polypeptides such as bortazomib, erythropoietin, interleukins ( e.g ., IL-1 , IL-2, IL-3, IL-6), leukemia inhibitory factor, interferons, romidepsin, thrombopoietin, TNF-a, CD30 ligand, 4-1 BB ligand, and Apo-1 ligand.
  • angiogeneisisisis inhibitors such as angiostatin, bevacizumab, denileukin
  • Non-limiting examples of photodynamic therapeutic agents include aminolevulinic acid, methyl aminolevulinate, retinoids (alitretinon, tamibarotene, tretinoin), and temoporfin.
  • antineoplastic agents include anagrelide, arsenic trioxide, asparaginase, bexarotene, bropirimine, celecoxib, chemically linked Fab, efaproxiral, etoglucid, ferruginol, lonidamide, masoprocol, miltefosine, mitoguazone, talapanel, trabectedin, and vorinostat.
  • chemotherapeutic agent can and will vary depending upon the agent and the type of tumor or neoplasm. Suitable modes of administration were detailed in Section 11(d), below. A skilled practitioner will be able to determine the appropriate dose of the chemotherapeutic agent.
  • the present disclosure encompasses a method of selectively killing one or more senescent cells in a sample, the method comprising contacting a composition comprising an effective amount of a compound of Formula (I), a compound of Formula (II), a senolytic agent or a combination thereof, with the sample.
  • the present disclosure encompasses a method of selectively killing one or more senescent cells in a subject in need thereof, the method comprising administering to the subject a composition comprising a therapeutically effective amount of a compound of Formula (I), a compound of Formula (II), a senolytic agent or a combination thereof.
  • the composition comprising an effective amount of a compound of Formula (I) or a compound of Formula (II) are less toxic to platelets when compared to a control sample or subject treated with ABT-263.
  • the present disclosure encompasses a method of selectively killing one or more cancer cells in a sample, the method comprising contacting a composition comprising an effective amount of a compound of Formula (I), a compound of Formula (II), a senolytic agent or a combination thereof with the sample.
  • the present disclosure encompasses a method of selectively killing one or more cancer cells in a subject in need thereof, the method comprising administering to the subject a composition comprising a therapeutically effective amount of a compound of Formula (I) or a compound of Formula (II).
  • the present disclosure encompasses a method of decreasing the senescence associated secretory phenotype of osteoblasts and/or osteocytes in a sample, the method comprising contacting a composition comprising an effective amount of a compound of Formula (I) or a compound of Formula (II) with the sample.
  • the present disclosure encompasses a method of decreasing the senescence associated secretory phenotype of osteoblasts and/or osteocytes in a subject in need thereof, the method comprising administering to the subject a composition comprising a therapeutically effective amount of a compound of Formula (I) or a compound of Formula (II).
  • the composition comprising an effective amount of a compound of Formula (I) or a compound of Formula (II) are less toxic to platelets when compared to a control sample or subject treated with ABT- 263.
  • the present disclosure encompasses a method of decreasing osteoclastogenesis in a sample, the method comprising contacting a composition comprising an effective amount of a compound of Formula (I) or a compound of Formula (II) with the sample.
  • the present disclosure encompasses a method of decreasing osteoclastogenesis in a subject in need thereof, the method comprising administering to the subject a composition comprising a therapeutically effective amount of a compound of Formula (I) or a compound of Formula (II).
  • the composition comprising an effective amount of a compound of Formula (I) or a compound of Formula (II) are less toxic to platelets when compared to a control sample or subject treated with ABT-263.
  • the median lethal dose or LD50 of the inhibitor in non- senescent cells may be about 5 to about 50 times higher than the LD50 of the inhibitor in senescent cells.
  • the LD50 is the concentration of inhibitor required to kill half the cells in the cell sample.
  • the LD50 of the inhibitor in non- senescent cells may be greater than about 5, about 6, about 7, about 8, about 9 or about 10 times higher than the LD50 of the inhibitor in senescent cells.
  • the LD50 of the inhibitor in non-senescent cells may be greater than about 10, about 15, about 20, about 25, about 30, about 35, about 40, about 45, or about 50 times higher than the LD50 of the inhibitor in senescent cells. Additionally, the LD50 of the inhibitor in non-senescent cells may be greater than 50 times higher than the LD50 of the inhibitor in senescent cells. In a specific embodiment, the LD50 of the inhibitor in non- senescent cells is greater than 10 times higher than the LD500 of the inhibitor in senescent cells. In another specific embodiment, the LD50 of the inhibitor in non- senescent cells is greater than 20 times higher than the LD50 of the inhibitor in senescent cells.
  • spontaneous also refers to the state into which cells enter after multiple rounds of division and, as a result of cellular pathways, future cell division is prevented from occurring even though the cell remains metabolically active.
  • Senescent cells may differ from their pre-senescent counterparts in one or more of the following ways: 1 ) they arrest growth and cannot be stimulated to reenter the cell cycle by physiological mitogens; 2) they become resistant to apoptotic cell death; and/or 3) they acquire altered differentiated functions.
  • TIS therapy-induced senescence
  • the number of senescent cells in various organs and tissues of a subject increases with age.
  • the accumulation of senescent cells may drive the deterioration that underlies aging and age-related diseases.
  • the accumulation of senescent cells in aged tissue may contribute to age-associated tissue dysfunction, reduced regenerative capacity, and disease.
  • senescence is considered deleterious because it contributes to decrements in tissue renewal and function.
  • an aged tissue may lack the ability to respond to stress when proliferation is required thereby resulting in the reduced fitness seen with aging.
  • a key component of this model is that substantial numbers of senescent cells should be present in tissues with aging, without, or prior to, pathology.
  • a senescent cell may be a cell that ceases to divide but remains metabolically active.
  • the non-dividing cells may remain viable for many weeks, but fail to grow/replicate DNA despite the presence of ample space, nutrients and growth factors in the medium.
  • the senescence growth arrest is essentially permanent because senescent cells cannot be stimulated to proliferate by known physiological stimuli.
  • a senescent cell of the invention may be resistant to certain apoptotic signals and may acquire widespread changes in gene expression. The resistance to apoptosis may explain the increase in senescent cells with age. Manipulation of pro- and anti-apoptotic proteins may cause cells that are destined to die by apoptosis to senesce and, conversely, cause cells that are destined to senesce to undergo apoptosis.
  • a senescent cell of the invention may be senescent due to replicative cellular senescence, premature cellular senescence or therapy-induced senescence.
  • Senescent cells that are senescent due to replication may have undergone greater than 60 population doublings.
  • senescent cells that are senescent due to replication may have undergone greater than 40, greater than 50, greater than 60, greater than 70 or greater than 80 population doublings.
  • a senescent cell that is prematurely cellular senescent may be induced by, but not limited to, ultraviolet light, reactive oxygen species, chemotherapeutics, environmental toxin, cigarette smoking, ionizing radiation, distortion of chromatin structure, excessive mitogenic signaling, and oncogenic mutations.
  • premature cellular senescence may be induced by ionizing radiation (IR). In another specific embodiment, premature cellular senescence may also be induced by ectopic transfection with Ras oncogene. A senescent cell that is therapy-induced senescent may have been exposed to DNA- damaging therapy.
  • IR ionizing radiation
  • premature cellular senescence may also be induced by ectopic transfection with Ras oncogene.
  • a senescent cell that is therapy-induced senescent may have been exposed to DNA- damaging therapy.
  • a senescent cell of the invention may generally be a eurkaryotic cell.
  • senescent cells may include, but are not limited to, mammary epithelial cells, keratinocytes, cardiac myocytes, chondrocytes, endothelial cells (large vessels), endothelial cells (microvascular), epithelial cells, fibroblasts, follicle dermal papilla cells, hepatocytes, melanocytes, osteoblasts, preadipocytes, primary cells of the immune system, skeletal muscle cells, smooth muscle cells, adipocytes, neurons, glial cells, contractile cells, exocrine secretory epithelial cells, extracellular matrix cells, hormone secreting cells, keratinizing epithelial cells, islet cells, lens cells, mesenchymal stem cells, pancreatic acinar cells, paneth cells of the small intestine, primary cells of hemopoietic linage, primary cells of the nervous system
  • the stem cells are adult stem cells.
  • Adult stem cells are stem cells which maintain and repair the tissue in which they are found and are generally referred to by their tissue of origin.
  • Non-limiting examples of adult stem cells include muscle stem cells, hematopoietic stem cells, heart stem cells, neural stem cells, mesenchymal stem cells, intestinal stem cells, skin stem cells, adipose-derived stem cells, endothelial stem cells, and dental pulp stem cells.
  • a senescent cell of the invention is a fibroblast.
  • a senescent cell may be a hematopoietic stem cell.
  • a senescent cell of the invention may be found in renewable tissues, including the vasculature, hematopoietic system, epithelial organs and the stroma.
  • a senescent cell of the invention may also be found at sites of aging or chronic age-related pathology, such as osteoarthritis and atherosclerosis.
  • a senescent cell of the invention may be associated with benign dysplastic or preneoplastic lesions and benign prostatic hyperplasia.
  • a senescent cell of the invention may be found in normal and tumor tissues following DNA-damaging therapy.
  • a senescent cell may be found at a site of aging or age-related pathology.
  • An age-related pathology may include any disease or condition which is fully or partially mediated by the induction or maintenance of a non-proliferating or senescent state in a cell or a population of cells in a subject.
  • Non-limiting examples include age-related tissue or organ decline which may lack visible indication of pathology, or overt pathology such as a degenerative disease or a function-decreasing disorder.
  • Alzheimer’s disease Parkinson’s disease, cataracts, macular degeneration, glaucoma, atherosclerosis, acute coronary syndrome, myocardial infarction, stroke, hypertension, idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease (COPD), osteoarthritis, type 2 diabetes, obesity, fat dysfunction, coronary artery disease, cerebrovascular disease, periodontal disease, and cancer treatment-related disability such as atrophy and fibrosis in various tissues, brain and heart injury, and therapy-related myelodysplastic syndromes.
  • IPF idiopathic pulmonary fibrosis
  • COPD chronic obstructive pulmonary disease
  • osteoarthritis type 2 diabetes
  • obesity obesity
  • fat dysfunction coronary artery disease
  • cerebrovascular disease cerebrovascular disease
  • periodontal disease periodontal disease
  • cancer treatment-related disability such as atrophy and fibrosis in various tissues, brain and heart injury, and therapy-related myelodysplastic syndromes.
  • an age- related pathology may include an accelerated aging disease such as progeroid syndromes (i.e., Hutchinson-Gilford progeria syndrome, Werner syndrome, Bloom syndrome, Rothmund-Thomson Syndrome, Cockayne syndrome, xeroderma pigmentosum, trichothiodystrophy, combined xeroderma pigmentosum-Cockayne syndrome, and restrictive dermopathy), ataxia telangiectasia, Fanconi anemia, Friedreich's ataxia, dyskeratosis congenital, aplastic anemia, IPF, and others.
  • a method of identifying an age-related disease or condition as described herein may include detecting the presence of senescent cells.
  • a method of the invention may comprise detecting senescent cells.
  • Senescent cells may be detected in vivo or in vitro. Suitable markers for detecting senescent cells in vitro and in vivo are known in the art.
  • methods to detect senescent cells may include, but are not limited to, detecting lack of DNA replication by incorporation of a DNA-staining reagent ⁇ e.g., 5-bromodeoxyuridine (BrdU), 3H-thymidine), immunostaining for proteins such as proliferating cell nuclear antigen (PCNA) and Ki-67, histochemical staining for senescence-associated b- galactosidase (SA- -gal), detecting expression of p16, p19, Pai 1 , Igfbp2, IL-6, Mmp13, Nrg1 , differentiated embryo-chondrocyte expressed-1 (DEC1 ), p15 (a CDK1 ) and decoy death receptor-2 (DCR2), detecting cytological markers such as senescence-associated heterochromatin foci (SAHFs) and senescence-associated DNA-damage foci (SDFs).
  • a DNA-staining reagent ⁇ e.g., 5-
  • SAHFs may be detected by the preferential binding of DNA dyes, such as 4’, 6- diamidino-2-phenylindole (DAPI), and the presence of certain heterochromatin- associated histone modifications ⁇ e.g., H3 Lys9 methylation) and proteins ⁇ e.g., heterochromatin protein-1 (HP1 )).
  • DNA dyes such as 4’, 6- diamidino-2-phenylindole (DAPI)
  • heterochromatin-associated histone modifications ⁇ e.g., H3 Lys9 methylation
  • proteins ⁇ e.g., heterochromatin protein-1 (HP1 )
  • senescent cells may be detected as described in US Patent No. 5,491 ,069 and US Patent Application No. 2010/0086941 .
  • senescent cells are detected by histochemical staining for SA-b- gal.
  • one or more senescent cells are detected in a sample.
  • a sample may be a cell sample, a tissue sample, or a biopsy from a subject.
  • a sample may be dependent on the age-related pathology.
  • a sample may be tissue biopsy material.
  • a tissue sample may be from esophagus, stomach, liver, gallbladder, pancreas, adrenal glands, bladder, gallbladder, large intestine, small intestine, kidneys, liver, pancreas, colon, stomach, thymus, spleen, brain, spinal cord, nerves, adipose tissue, heart, lungs, eyes, corneal, skin or islet tissue or organs.
  • a tissue sample may be from lung, skeletal muscle, and brain. In another specific embodiment, a tissue sample may be from liver and heart. Alternatively, a sample may be a cell sample. As such, a cell sample may be oocytes and/or spermatozoa, mesenchymal stem cells, adipocytes, central nervous system neurons and glial cells, contractile cells, exocrine secretory epithelial cells, extracellular matrix cells, hormone secreting cells, keratinizing epithelial cells, islet cells, kidney cells, lens cells, pancreatic acinar cells, paneth cells of small intestine, primary cells of hemopoietic lineage, primary cells of the nervous system, sense organ and peripheral neuron supporting cells or wet stratified barrier epithelial cells. Detection of senescent cells may be used to assess the replicative history of tissues, thereby providing a method for evaluation of the physiological, in contrast to the chronological age of the tissue.
  • the number of senescent cells may increase with age.
  • the number of senescent cells in a tissue or sample may be from less than 1 % to greater than 15%. In an embodiment, the number of senescent cells in a tissue or sample may be less than 1 %, less than 2%, less than 3%, less than 4%, or less than 5%. In another
  • the number of senescent cells in a tissue or sample may be about 5%, about 6%, about 7%, about 8%, about 9%, or about 10%. In still another embodiment, the number of senescent cells in a tissue or sample may be greater than 10%, greater than 1 1 %, greater than 12%, greater than 13%, greater than 14%, or greater than 15%.
  • a method of the invention may comprise measuring cell death of senescent cells.
  • Methods of measuring cell death are known in the art.
  • cell death may be measured by Giemsa staining, trypan blue exclusion, acridine orange/ethidium bromide (AO/EB) double staining for fluorescence microscopy and flow cytometry, propidium iodide (PI) staining, annexin V assay, TUNEL assay,
  • cell death is due to induction of apoptosis.
  • Cell death due to induction of apoptosis may be measured by observation of morphological characteristics including cell shrinkage, cytoplasmic condensation, chromatin segregation and condensation, membrane blebbing, and the formation of membrane-bound apoptotic bodies.
  • Cell death due to induction of apoptosis may be measured by observation of biochemical hallmarks including internucleosomal DNA cleavage into oligonucleosome-length fragments.
  • Traditional cell-based methods of measuring cell death due to induction of apoptosis include light and electron microscopy, vital dyes, and nuclear stains.
  • Biochemical methods include DNA laddering, lactate dehydrogenase enzyme release, and MTT/XTT enzyme activity. Additionally, terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling of DNA fragments (TUNEL) and in situ end labeling (ISEL) techniques are used, which when used in conjunction with standard flow cytometric staining methods yield informative data relating cell death to various cellular parameters, including cell cycle and cell phenotype. See Loo and Rillema, Methods Cell Biol. 1998;57:251 -64, which is incorporated herein by reference, for a review of these methods.
  • TUNEL terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling of DNA fragments
  • ISEL in situ end labeling
  • cell death due to apoptosis may be measured by the reduction of procaspase-3.
  • Caspase-3 has been implicated as an“effector” caspase associated with the initiation of the“death cascade” and is therefore an important marker of the cell’s entry point into the apoptotic signaling pathway.
  • Caspase-3 is activated by the upstream caspase-8 and caspase-9, and since it serves as a convergence point for different signaling pathways, it is well suited as a read-out in an apoptosis assay.
  • cell death may be measured as a reduction in viable cells. Since a composition of the invention selectively kills senescent cells, a reduction in viable cells is indicative of a reduction in senescent cells. As described in Section lll(b), the number of senescent cells in a sample may be from less than 1 % to greater than 15%. As such, a reduction in viable cells following administration of an inhibitor of the invention may be greater than 15% to less than 1 %. For example, the reduction in viable cells may be less than 1 %, less than 2%, less than 3%, less than 4%, or less than 5%.
  • the reduction in viable cells may be about 5%, about 6%, about 7%, about 8%, about 9%, or about 10%. Additionally, the reduction in viable cells may be greater than 10%, greater than 1 1 %, greater than 12%, greater than 13%, greater than 14%, or greater than 15%.
  • a therapeutically effective amount of a composition of the invention may be administered to a subject.
  • Administration is performed using standard effective techniques, including peripherally (/.e., not by administration into the central nervous system) or locally to the central nervous system.
  • Peripheral administration includes but is not limited to oral, inhalation, intravenous, intraperitoneal, intra-articular, subcutaneous, pulmonary, transdermal, intramuscular, intranasal, buccal, sublingual, or suppository administration.
  • Local administration, including directly into the central nervous system (CNS) includes but is not limited to via a lumbar, intraventricular or intraparenchymal catheter or using a surgically implanted controlled release formulation.
  • the route of administration may be dictated by the disease or condition to be treated.
  • the composition may be administered via inhalation.
  • the disease or condition is osteoarthritis
  • the composition may be administered via intra-articular invention. It is within the skill of one in the art, to determine the route of administration based on the disease or condition to be treated.
  • a composition of the invention is administered orally.
  • compositions for effective administration are deliberately designed to be appropriate for the selected mode of administration, and pharmaceutically acceptable excipients such as compatible dispersing agents, buffers, surfactants, preservatives, solubilizing agents, isotonicity agents, stabilizing agents and the like are used as appropriate.
  • pharmaceutically acceptable excipients such as compatible dispersing agents, buffers, surfactants, preservatives, solubilizing agents, isotonicity agents, stabilizing agents and the like are used as appropriate.
  • a therapeutically effective amount of a composition of the invention is administered to a subject.
  • A“therapeutically effective amount” is an amount of the therapeutic composition sufficient to produce a measurable response (e.g., cell death of senescent cells, an anti-aging response, an improvement in symptoms associated with a degenerative disease, or an improvement in symptoms associated with a function-decreasing disorder).
  • a measurable response e.g., cell death of senescent cells, an anti-aging response, an improvement in symptoms associated with a degenerative disease, or an improvement in symptoms associated with a function-decreasing disorder.
  • Actual dosage levels of active ingredients in a therapeutic composition of the invention can be varied so as to administer an amount of the active compound(s) that is effective to achieve the desired therapeutic response for a particular subject.
  • the selected dosage level will depend upon a variety of factors including the activity of the therapeutic composition, formulation, the route of administration, combination with other drugs or treatments, age, the age-related disease or condition, the degenerative disease, the function- decreasing disorder, the symptoms, and the physical condition and prior medical history of the subject being treated.
  • a minimal dose is administered, and dose is escalated in the absence of dose-limiting toxicity. Determination and adjustment of a therapeutically effective dose, as well as evaluation of when and how to make such adjustments, are known to those of ordinary skill in the art of medicine.
  • a composition comprising an effective amount of a compound of Formula (I), a compound of Formula (II), a senolytic agent or a combination thereof is administered directly to the target tissue or organ comprising senescent cells that contribute to manifestation of the disease or disorder.
  • a composition comprising an effective amount of a compound of Formula (I), a compound of Formula (II), a senolytic agent or a combination thereof is administered directly to an osteoarthritic joint (i.e., intra- articularly) of a subject in need thereof.
  • a composition comprising an effective amount of a compound of Formula (I), a compound of Formula (II), a senolytic agent or a combination thereof may be administered to the joint via topical, transdermal, intradermal, or subcutaneous route.
  • methods are provided herein for treating a cardiovascular disease or disorder associated with arteriosclerosis, such as atherosclerosis by administering directly into an artery.
  • compositions comprising an effective amount of a compound of Formula (I), a compound of Formula (II), a senolytic agent or a combination thereof for treating a senescent- associated pulmonary disease or disorder may be administered by inhalation, intranasally, by intubation, or intracheally, for example, to provide the senolytic agent more directly to the affected pulmonary tissue.
  • a composition comprising an effective amount of a compound of Formula (I), a compound of Formula (II), a senolytic agent or a combination thereof may be delivered directly to the eye either by injection (e.g., intraocular or intravitreal) or by conjunctival application underneath an eyelid of a cream, ointment, gel, or eye drops.
  • a composition comprising an effective amount of a compound of Formula (I), a compound of Formula (II), a senolytic agent or a combination thereof may be formulated as a timed release (also called sustained release, controlled release) composition or may be administered as a bolus infusion.
  • the frequency of dosing may be daily or once, twice, three times or more per week or per month, as needed as to effectively treat the symptoms.
  • the timing of administration of the treatment relative to the disease itself and duration of treatment will be determined by the circumstances surrounding the case.
  • Treatment could begin immediately, such as at the site of the injury as administered by emergency medical personnel.
  • Treatment could begin in a hospital or clinic itself, or at a later time after discharge from the hospital or after being seen in an outpatient clinic.
  • Duration of treatment could range from a single dose administered on a one-time basis to a life-long course of therapeutic treatments. Treatment may be before or after onset of the disease or disease symptoms.
  • Typical dosage levels can be determined and optimized using standard clinical techniques and will be dependent on the mode of administration.
  • a subject may be a rodent, a human, a livestock animal, a companion animal, or a zoological animal.
  • the subject may be a rodent (e.g ., a mouse, a rat, a guinea pig, etc.).
  • the subject may be a livestock animal.
  • suitable livestock animals may include pigs, cows, horses, goats, sheep, llamas and alpacas.
  • the subject may be a companion animal.
  • companion animals may include pets such as dogs, cats, rabbits, and birds.
  • the subject may be a zoological animal.
  • a“zoological animal” refers to an animal that may be found in a zoo. Such animals may include non-human primates, large cats, wolves, and bears.
  • the subject is a human.
  • the human subject may be of any age. However, since senescent cells are normally associated with aging, a human subject may be an older human subject. In some embodiments, the human subject may be about 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95 years of age or older. In some preferred embodiments, the human subject is 30 years of age or older. In other preferred embodiments, the human subject is 40 years of age or older. In other preferred embodiments, the human subject is 45 years of age or older. In yet other preferred embodiments, the human subject is 50 years of age or older. In still other preferred embodiments, the human subject is 55 years of age or older. In other preferred embodiments, the human subject is 60 years of age or older.
  • the human subject is 65 years of age or older. In still other preferred embodiments, the human subject is 70 years of age or older. In other preferred embodiments, the human subject is 75 years of age or older. In still other preferred embodiments, the human subject is 80 years of age or older. In yet other preferred embodiments, the human subject is 85 years of age or older. In still other preferred embodiments, the human subject is 90 years of age or older.
  • a subject in need thereof may be a subject suffering from an age-related disease or condition as described below.
  • senescent cells drive age-related pathologies and that selective elimination of these cells can prevent or delay age- related deterioration.
  • senescent cells may be therapeutic targets in the treatment of aging and age-related disease.
  • removal of senescent cells may delay tissue dysfunction and extend health span. Clearance of senescent cells is expected to improve tissue milieu, thereby improving the function of the remaining non-senescent cells.
  • the present disclosure provides a method for delaying at least one feature of aging in a subject, the method comprising administering a composition comprising a therapeutically effective amount of a compound of Formula (I) or a compound of Formula (II) to a subject.
  • a feature of aging may include, but is not limited to, systemic decline of the immune system, muscle atrophy and decreased muscle strength, decreased skin elasticity, delayed wound healing, retinal atrophy, reduced lens transparency, reduced hearing, osteoporosis, sarcopenia, hair graying, skin wrinkling, poor vision, frailty, and cognitive impairment.
  • a composition of in the invention selectively kills senescent cells.
  • targeting senescent cells during the course of aging may be a preventative strategy. Accordingly, administration of a composition comprising a therapeutically effective amount of a compound of Formula (I) or a compound of Formula (II) to a subject may prevent comorbidity and delay mortality in an older subject. Further, selective killing of senescent cells may boost the immune system, extend the health span, and improve the quality of life in a subject. Additionally, selective killing of senescent cells may delay sarcopenia. Sarcopenia is the
  • a delay in sarcopenia may reduce frailty, reduce risk of falling, reduce fractures, and reduce functional disability in a subject.
  • selective killing of senescent cells may delay aging of the skin. Aged skin has increased wrinkles, decreased immune barrier function and increased susceptibility to skin cancer and trauma. As such, selective killing of senescent cells may delay skin wrinkling, delay the onset of decreased immune barrier function and decrease susceptibility to skin cancer and trauma in a subject. Selective killing of senescent cells may also delay the onset of retinal atrophy and reduced lens transparency as measured by vision tests.
  • aging may be measured in the bone by incident non-vertebral fractures, incident hip fractures, incident total fractures, incident vertebral fractures, incident repeat fractures, functional recovery after fracture, bone mineral density decrease at the lumbar spine and hip, rate of knee buckling, NSAID use, number of joints with pain, and osteoarthritis. Aging may also be measured in the muscle by functional decline, rate of falls, reaction time and grip strength, muscle mass decrease at upper and lower extremities, and dual tasking 1 0-meter gait speed. Further, aging may be measured in the cardiovascular system by systolic and diastolic blood pressure change, incident hypertension, major
  • cardiovascular events such as myocardial infarction, stroke, congestive heart disease, and cardiovascular mortality.
  • aging may be measured in the brain by cognitive decline, incident depression, and incident dementia.
  • aging may be measured in the immune system by rate of infection, rate of upper respiratory infections, rate of flu-like illness, incident severe infections that lead to hospital admission, incident cancer, rate of implant infections, and rate of gastrointestinal infections.
  • Other indications of aging may include, but not limited to, decline in oral health, tooth loss, rate of Gl symptoms, change in fasting glucose and/or insulin levels, body composition, decline in kidney function, quality of life, incident disability regarding activities of daily living, and incident nursing home admission.
  • Methods of measuring skin aging are known in the art and may include trans-epidermal water loss (TEWL), skin hydration, skin elasticity, area ratio analysis of crow’s feet, sensitivity, radiance, roughness, spots, laxity, skin tone homogeneity, softness, and relief (variations in depth).
  • TEWL trans-epidermal water loss
  • skin hydration skin hydration
  • skin elasticity skin elasticity
  • area ratio analysis of crow’s feet sensitivity, radiance, roughness, spots, laxity, skin tone homogeneity, softness, and relief (variations in depth).
  • the present disclosure also provides a method of treating an age- related disease or condition, the method comprising administering a composition comprising a therapeutically effective amount of a compound of Formula (I) or a compound of Formula (II) to a subject in need thereof, provided the age-related disease or condition is not cancer.
  • “age-related disease or condition” may include, but is not limited to, a degenerative disease or a function-decreasing disorder such as Alzheimer’s disease, Parkinson’s disease, cataracts, macular degeneration, glaucoma, atherosclerosis, acute coronary syndrome, myocardial infarction, stroke, hypertension, idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease (COPD), osteoporosis, osteoarthritis, type 2 diabetes, obesity, fat dysfunction, coronary artery disease, cerebrovascular disease, periodontal disease, cancer treatment-related disability such as atrophy and fibrosis in various tissues, brain and heart injury, and therapy-related myelodysplastic syndromes, and diseases associated with accelerated aging and/or defects in DNA damage repair and telomere maintenance such as progeroid syndromes (i.e., Hutchinson-Gilford progeria syndrome, Werner syndrome, Bloom syndrome, Rothmund-Thomson Syndrome, Cockayne syndrome
  • compositions and methods include those described herein in any of their pharmaceutically acceptable forms, including isomers such as diastereomers and enantiomers, salts, solvates, and polymorphs, as well as racemic mixtures and pure isomers of the compounds described herein, where applicable.
  • Bcl-2 as used herein alone or as part of a group references to a member of the Bcl-2 family of proteins comprise the following BCI-XL, MCL-1 , Bcl-W, BFL-1 /A1 , Bcl-B, BAX, BAK, and BOK.
  • Alkyl refers to saturated monovalent hydrocarbon radicals having straight or branched hydrocarbon chains or, in the event that at least 3 carbon atoms are present, cyclic hydrocarbons or combinations thereof and contains 1 to 20 carbon atoms (C 1 -C 20 alkyl), suitably 1 to 1 0 carbon atoms (C 1 -C 10 alkyl), preferably 1 to 8 carbon atoms (CrC 8 alkyl), more preferably 1 to 6 carbon atoms (C 1 -C 4 alkyl), and even more preferably 1 to 4 carbon atoms (C 1 -C 4 alkyl).
  • alkyl radicals include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec- butyl, tert-butyl, pentyl, isoamyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
  • Aryl as used herein, alone or as part of a group, includes an organic radical derived from an aromatic hydrocarbon by removal of one hydrogen, and includes monocyclic and polycyclic radicals, such as phenyl, biphenyl, naphthyl.
  • Cycloalkyl as used herein, alone or in combination, means a saturated or partially saturated monocyclic, bicyclic or tricyclic alkyl radical wherein each cyclic moiety contains from about 3 to about 8 carbon atoms, more preferably from about 3 to about 6 carbon atoms. Examples of such cycloalkyl radicals include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
  • Heteroatom means an atom other than carbon e.g., in the ring of a heterocyclic group or the chain of a heterogeneous group.
  • heteroatoms are selected from the group consisting of sulfur, phosphorous, nitrogen, and oxygen atoms.
  • Groups containing more than one heteroatom may contain different heteroatoms.
  • Heteroaryl as used herein, along or in combination, includes an organic radical derived from an aromatic hydrocarbon by removal of one hydrogen and includes at least one heteroatom.
  • heteroaryl includes pyrrole, thiophene, furan, indole, pyrazine, pyridine, triazole, imidazole, thiazole, oxazole and the like.
  • Substituted means that one or more of the hydrogen atoms bonded to carbon atoms in the chain or ring have been replaced with other substituents.
  • Suitable substituents include monovalent hydrocarbon groups including alkyl groups such as methyl groups and monovalent heterogeneous groups including alkoxy groups such as methoxy groups. "Unsubstituted" means that the carbon chain or ring contains no other substituents other than carbon and hydrogen.
  • Branched means that the carbon chain is not simply a linear chain.
  • Unbranched means that the carbon chain is a linear carbon chain.
  • Heteroatom means an atom other than carbon e.g., in the ring of a heterocyclic group or the chain of a heterogeneous group.
  • heteroatoms are selected from the group consisting of sulfur, phosphorous, nitrogen and oxygen atoms.
  • Groups containing more than one heteroatom may contain different heteroatoms.
  • Heterocyclic group means a saturated or unsaturated ring structure containing carbon atoms and 1 or more heteroatoms in the ring. Heterocyclic groups are not aromatic. Heterocyclic groups are monocyclic or polycyclic. Polycyclic heteroaromatic groups can be fused, spiro, or bridged ring systems. Monocyclic heterocyclic groups contain 4 to 10 member atoms (i.e., including both carbon atoms and at least 1 heteroatom), suitably 4 to 7, and more suitably 5 to 6 in the ring. Bicyclic heterocyclic groups contain 8 to 18 member atoms, suitably 9 or 10 in the rings.
  • Said mixture may contain all diastereoisomers, epimers, enantiomers and/or conformers of the basic molecular structure of said compound.
  • stereogenic centers may have the R- or S-configuration
  • diastereoisomers may have a syn- or anti-configuration
  • substituents on bivalent cyclic saturated radicals may have either the cis- or trans-configuration
  • alkenyl radicals may have the E- or Z-configuration. All stereochemically isomeric forms of said compound both in pure form or in admixture with each other are intended to be embraced within the scope of the present invention.
  • the compounds of the present invention may be prepared in a number of ways well known to one skilled in the art of organic synthesis. More specifically, the novel compounds of this invention may be prepared using the reactions and techniques described herein. In the description of the synthetic methods described below, it is to be understood that all proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment and workup procedures, are chosen to be the conditions standard for that reaction. It is understood by one skilled in the art of organic synthesis that the functionality present on various portions of the molecule must be compatible with the reagents and reactions proposed. Such restrictions to the substituents, which are not compatible with the reaction conditions, will be apparent to one skilled in the art and alternate methods must then be used.
  • the starting materials for the examples contained herein are either commercially available or are readily prepared by standard methods from known materials.
  • the compounds of Formula (I) or Formula (II) may be synthesized through standard organic chemistry methodology and purification known to those trained in the art of organic synthesis by using commercially available starting materials and reagents.
  • Zinc powder (960 mg) was added to a mixture of compound 34 (316 mg) and AcOH (600 mI_) in 20 ml. THF. The reaction was stirred at room temperature for 5 hours. The solid was removed by filtration and the filtrate was poured into water and extracted with EtOAc. The organic phase was washed with brine x1 , dried over Na 2 S0 4 , filtered and evaporated to dryness. The crude product was purified via column chromatography using DCM, methanol, and TEA as eluents to afford 210 mg compound 35. Yield 78%.
  • HATU (30 mg) was added to a mixture of compound 35 (50 mg), 4- azidobutanoic acid (6.7 mg), DIPEA (13.5 mI_) in 2 ml. DCM. The mixture was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure and the crude product was purified via column chromatography using DCM and methanol as eluents to afford 40 mg compound 36. Yield 72%.

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Abstract

La présente invention concerne des compositions et des procédés permettant la destruction sélective de cellules sénescentes, la composition comprenant un composé de formule (I) ou un composé de formule (II). La destruction sélective de cellules sénescentes peut retarder le vieillissement et/ou traiter des troubles liés à l'âge.
PCT/US2019/056837 2016-04-21 2019-10-17 Compositions ciblant des cellules sénescentes et leurs utilisations Ceased WO2020081880A1 (fr)

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WO2025136208A1 (fr) 2023-12-21 2025-06-26 Hadjab Saida Composés sénolytiques destinés à être utilisés dans le traitement et/ou la prévention d'un trouble de la céphalée et/ou de la douleur chronique

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EP3177144A4 (fr) 2014-07-22 2018-01-24 Bioventures, LLC. Compositions et procédés de déplétion sélective de cellules sénescentes
KR102447884B1 (ko) * 2016-04-21 2022-09-27 바이오벤처스, 엘엘씨 항-세포자멸적 bcl-2 계열 단백질의 열화를 유도하는 화합물 및 이의 용도
KR20250044800A (ko) 2016-10-11 2025-04-01 아비나스 오퍼레이션스, 인코포레이티드 안드로겐 수용체의 표적 분해용 화합물 및 방법
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